Editing Bioinformatics (section)

==Sequence analysis==
{{main|Sequence alignment|Sequence database|Alignment-free sequence analysis}}
Since the bacteriophage [[Phi X 174|Phage Φ-X174]] was [[sequenced]] in 1977,<ref name="pmid870828">{{cite journal | vauthors = Sanger F, Air GM, Barrell BG, Brown NL, Coulson AR, Fiddes CA, Hutchison CA, Slocombe PM, Smith M | title = Nucleotide sequence of bacteriophage phi X174 DNA | journal = Nature | volume = 265 | issue = 5596 | pages = 687–95 | date = February 1977 | pmid = 870828 | doi = 10.1038/265687a0 | s2cid = 4206886 | bibcode = 1977Natur.265..687S }}</ref> the [[DNA sequence]]s of thousands of organisms have been decoded and stored in databases. This sequence information is analyzed to determine genes that encode [[protein]]s, RNA genes, regulatory sequences, structural motifs, and repetitive sequences. A comparison of genes within a [[species]] or between different species can show similarities between protein functions, or relations between species (the use of [[molecular systematics]] to construct [[phylogenetic tree]]s). With the growing amount of data, it long ago became impractical to analyze DNA sequences manually. [[Computer program]]s such as [[BLAST (biotechnology)|BLAST]] are used routinely to search sequences—as of 2008, from more than 260,000 organisms, containing over 190 billion [[nucleotide]]s.<ref name="pmid18073190">{{cite journal | vauthors = Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Wheeler DL | title = GenBank | journal = Nucleic Acids Research | volume = 36 | issue = Database issue | pages = D25-30 | date = January 2008 | pmid = 18073190 | pmc = 2238942 | doi = 10.1093/nar/gkm929 }}</ref>

===DNA sequencing===
{{main|DNA sequencing}}

Before sequences can be analyzed, they are obtained from a data storage bank, such as GenBank. [[DNA sequencing]] is still a non-trivial problem as the raw data may be noisy or affected by weak signals. [[Algorithm]]s have been developed for [[base calling]] for the various experimental approaches to DNA sequencing.

[[File:Sequencing analysis steps.png|center|600px|Image: 450 pixels Sequencing analysis steps]]

===Sequence assembly===
{{main|Sequence assembly}}
Most DNA sequencing techniques produce short fragments of sequence that need to be assembled to obtain complete gene or genome sequences. The [[shotgun sequencing]] technique (used by [[The Institute for Genomic Research]] (TIGR) to sequence the first bacterial genome, ''[[Haemophilus influenzae]]'')<ref name="pmid7542800">{{cite journal | vauthors = Fleischmann RD, Adams MD, White O, Clayton RA, Kirkness EF, Kerlavage AR, Bult CJ, Tomb JF, Dougherty BA, Merrick JM | title = Whole-genome random sequencing and assembly of Haemophilus influenzae Rd | journal = Science | volume = 269 | issue = 5223 | pages = 496–512 | date = July 1995 | pmid = 7542800 | doi = 10.1126/science.7542800 | bibcode = 1995Sci...269..496F }}</ref> generates the sequences of many thousands of small DNA fragments (ranging from 35 to 900 nucleotides long, depending on the sequencing technology). The ends of these fragments overlap and, when aligned properly by a genome assembly program, can be used to reconstruct the complete genome. Shotgun sequencing yields sequence data quickly, but the task of assembling the fragments can be quite complicated for larger genomes. For a genome as large as the [[human genome]], it may take many days of CPU time on large-memory, multiprocessor computers to assemble the fragments, and the resulting assembly usually contains numerous gaps that must be filled in later. Shotgun sequencing is the method of choice for virtually all genomes sequenced (rather than chain-termination or chemical degradation methods), and genome assembly algorithms are a critical area of bioinformatics research.

{{see also|sequence analysis|sequence mining|sequence profiling tool|sequence motif}}

===Genome annotation===
{{main|Gene prediction}}

In [[genomics]], [[Genome project#Genome annotation|annotation]] refers to the process of marking the stop and start regions of genes and other biological features in a sequenced DNA sequence. Many genomes are too large to be annotated by hand. As the rate of [[DNA sequencing|sequencing]] exceeds the rate of genome annotation, genome annotation has become the new bottleneck in bioinformatics.{{When|date=June 2023}}

Genome annotation can be classified into three levels: the [[nucleotide]], protein, and process levels.

Gene finding is a chief aspect of nucleotide-level annotation. For complex genomes, a combination of [[ab initio]] gene prediction and sequence comparison with expressed sequence databases and other organisms can be successful. Nucleotide-level annotation also allows the integration of genome sequence with other genetic and physical maps of the genome.

The principal aim of protein-level annotation is to assign function to the [[protein]] products of the genome. Databases of protein sequences and functional domains and motifs are used for this type of annotation. About half of the predicted proteins in a new genome sequence tend to have no obvious function.

Understanding the function of genes and their products in the context of cellular and organismal physiology is the goal of process-level annotation. An obstacle of process-level annotation has been the inconsistency of terms used by different model systems. The Gene Ontology Consortium is helping to solve this problem.<ref>{{cite journal |title=Genome annotation: from sequence to biology |journal=Nature |year=2001 |doi=10.1038/35080529|last1=Stein |first1=Lincoln |volume=2 |issue=7 |pages=493–503 |pmid=11433356 |s2cid=12044602 }}</ref>

The first description of a comprehensive annotation system was published in 1995<ref name="pmid7542800" /> by [[The Institute for Genomic Research]], which performed the first complete sequencing and analysis of the genome of a free-living (non-[[symbiotic]]) organism, the bacterium ''[[Haemophilus influenzae]]''.<ref name="pmid7542800" /> The system identifies the genes encoding all proteins, transfer RNAs, ribosomal RNAs, in order to make initial functional assignments. The [[GeneMark]] program trained to find protein-coding genes in ''[[Haemophilus influenzae]]'' is constantly changing and improving.

Following the goals that the Human Genome Project left to achieve after its closure in 2003, the [[ENCODE]] project was developed by the [[National Human Genome Research Institute]]. This project is a collaborative data collection of the functional elements of the human genome that uses next-generation DNA-sequencing technologies and genomic tiling arrays, technologies able to automatically generate large amounts of data at a dramatically reduced per-base cost but with the same accuracy (base call error) and fidelity (assembly error).

==== Gene function prediction ====
While genome annotation is primarily based on sequence similarity (and thus [[Homology (biology)|homology]]), other properties of sequences can be used to predict the function of genes. In fact, most ''gene'' function prediction methods focus on ''protein'' sequences as they are more informative and more feature-rich. For instance, the distribution of hydrophobic [[amino acid]]s predicts [[Transmembrane domain|transmembrane segments]] in proteins. However, protein function prediction can also use external information such as gene (or protein) [[Gene expression|expression]] data, [[protein structure]], or [[protein-protein interactions]].<ref>{{cite journal |vauthors=Erdin S, Lisewski AM, Lichtarge O |title=Protein function prediction: towards integration of similarity metrics |journal=Current Opinion in Structural Biology |volume=21 |issue=2 |pages=180–8 |date=April 2011 |pmid=21353529 |pmc=3120633 |doi=10.1016/j.sbi.2011.02.001}}</ref>

===Computational evolutionary biology===
{{further|Computational phylogenetics}}

[[Evolutionary biology]] is the study of the origin and descent of [[species]], as well as their change over time. [[Informatics]] has assisted evolutionary biologists by enabling researchers to:
* trace the evolution of a large number of organisms by measuring changes in their [[DNA]], rather than through physical taxonomy or physiological observations alone,
* compare entire [[genomes]], which permits the study of more complex evolutionary events, such as [[gene duplication]], [[horizontal gene transfer]], and the prediction of factors important in bacterial [[speciation]],
* build complex computational [[population genetics]] models to predict the outcome of the system over time<ref>{{cite journal | vauthors = Carvajal-Rodríguez A | title = Simulation of genes and genomes forward in time | journal = Current Genomics | volume = 11 | issue = 1 | pages = 58–61 | date = March 2010 | pmid = 20808525 | pmc = 2851118 | doi = 10.2174/138920210790218007 }}</ref>
* track and share information on an increasingly large number of species and organisms

===Comparative genomics===
{{main|Comparative genomics}}

The core of comparative genome analysis is the establishment of the correspondence between [[genes]] ([[Homology (biology)#Orthology|orthology]] analysis) or other genomic features in different organisms. Intergenomic maps are made to trace the evolutionary processes responsible for the divergence of two genomes. A multitude of evolutionary events acting at various organizational levels shape genome evolution. At the lowest level, point mutations affect individual nucleotides. At a higher level, large chromosomal segments undergo duplication, lateral transfer, inversion, transposition, deletion and insertion.<ref>{{cite book | vauthors = Brown TA |title=Genomes |date=2002 |publisher=Oxford |location=Manchester (UK) |edition=2nd |chapter=Mutation, Repair and Recombination}}</ref> Entire genomes are involved in processes of hybridization, polyploidization and [[endosymbiosis]] that lead to rapid speciation. The complexity of genome evolution poses many exciting challenges to developers of mathematical models and algorithms, who have recourse to a spectrum of algorithmic, statistical and mathematical techniques, ranging from exact, [[heuristics]], fixed parameter and [[approximation algorithms]] for problems based on parsimony models to [[Markov chain Monte Carlo]] algorithms for [[Bayesian analysis]] of problems based on probabilistic models.

Many of these studies are based on the detection of [[sequence homology]] to assign sequences to [[protein families]].<ref>{{cite journal | vauthors = Carter NP, Fiegler H, Piper J | title = Comparative analysis of comparative genomic hybridization microarray technologies: report of a workshop sponsored by the Wellcome Trust | journal = Cytometry | volume = 49 | issue = 2 | pages = 43–8 | date = October 2002 | pmid = 12357458 | doi = 10.1002/cyto.10153 }}</ref>

===Pan genomics===
{{main|Pan-genome}}

Pan genomics is a concept introduced in 2005 by Tettelin and Medini. Pan genome is the complete gene repertoire of a particular [[monophyletic]] taxonomic group. Although initially applied to closely related strains of a species, it can be applied to a larger context like genus, phylum, etc. It is divided in two parts: the Core genome, a set of genes common to all the genomes under study (often housekeeping genes vital for survival), and the Dispensable/Flexible genome: a set of genes not present in all but one or some genomes under study. A bioinformatics tool BPGA can be used to characterize the Pan Genome of bacterial species.<ref>{{cite journal | vauthors = Chaudhari NM, Gupta VK, Dutta C | title = BPGA- an ultra-fast pan-genome analysis pipeline | journal = Scientific Reports | volume = 6 | pages = 24373 | date = April 2016 | pmid = 27071527 | pmc = 4829868 | doi = 10.1038/srep24373 | bibcode = 2016NatSR...624373C }}</ref>

===Genetics of disease===
{{main|Genome-wide association studies}}

As of 2013, the existence of efficient high-throughput next-generation sequencing technology allows for the identification of cause many different human disorders. Simple [[Mendelian inheritance]] has been observed for over 3,000 disorders that have been identified at the [[Online Mendelian Inheritance in Man]] database, but complex diseases are more difficult. Association studies have found many individual genetic regions that individually are weakly associated with complex diseases (such as [[infertility]],<ref name="Demerec1945">{{cite journal | vauthors = Aston KI | title = Genetic susceptibility to male infertility: news from genome-wide association studies | journal = Andrology | volume = 2 | issue = 3 | pages = 315–21 | date = May 2014 | pmid = 24574159 | doi = 10.1111/j.2047-2927.2014.00188.x | s2cid = 206007180 | doi-access = free }}</ref> [[breast cancer]]<ref name="Véron2013">{{cite journal | vauthors = Véron A, Blein S, Cox DG | title = Genome-wide association studies and the clinic: a focus on breast cancer | journal = Biomarkers in Medicine | volume = 8 | issue = 2 | pages = 287–96 | year = 2014 | pmid = 24521025 | doi = 10.2217/bmm.13.121 }}</ref> and [[Alzheimer's disease]]<ref name="Tosto2013">{{cite journal | vauthors = Tosto G, Reitz C | title = Genome-wide association studies in Alzheimer's disease: a review | journal = Current Neurology and Neuroscience Reports | volume = 13 | issue = 10 | pages = 381 | date = October 2013 | pmid = 23954969 | pmc = 3809844 | doi = 10.1007/s11910-013-0381-0 }}</ref>), rather than a single cause.<ref name="Londin2013">{{Cite book |vauthors=Londin E, Yadav P, Surrey S, Kricka LJ, Fortina P |chapter=Use of linkage analysis, genome-wide association studies, and next-generation sequencing in the identification of disease-causing mutations |title=Pharmacogenomics |volume=1015 |pages=127–46 |year=2013 |pmid=23824853 |doi=10.1007/978-1-62703-435-7_8 |isbn=978-1-62703-434-0 |series=Methods in Molecular Biology }}</ref><ref>{{cite journal | vauthors = Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA | title = Potential etiologic and functional implications of genome-wide association loci for human diseases and traits | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 23 | pages = 9362–7 | date = June 2009 | pmid = 19474294 | pmc = 2687147 | doi = 10.1073/pnas.0903103106 | doi-access = free | bibcode = 2009PNAS..106.9362H }}</ref> There are currently many challenges to using genes for diagnosis and treatment, such as how we don't know which genes are important, or how stable the choices an algorithm provides.<ref>{{Cite book | vauthors = Hall LO |title=2010 International Conference on System Science and Engineering |chapter=Finding the right genes for disease and prognosis prediction |date=2010 |pages=1–2 |doi=10.1109/ICSSE.2010.5551766|isbn=978-1-4244-6472-2 |s2cid=21622726 }}</ref>

Genome-wide association studies have successfully identified thousands of common genetic variants for complex diseases and traits; however, these common variants only explain a small fraction of heritability.<ref>{{cite journal |last1=Manolio |first1=Teri A. |last2=Collins |first2=Francis S. |last3=Cox |first3=Nancy J. |last4=Goldstein |first4=David B. |last5=Hindorff |first5=Lucia A. |last6=Hunter |first6=David J. |last7=McCarthy |first7=Mark I. |last8=Ramos |first8=Erin M. |last9=Cardon |first9=Lon R. |last10=Chakravarti |first10=Aravinda |last11=Cho |first11=Judy H. |last12=Guttmacher |first12=Alan E. |last13=Kong |first13=Augustine |last14=Kruglyak |first14=Leonid |last15=Mardis |first15=Elaine |last16=Rotimi |first16=Charles N. |last17=Slatkin |first17=Montgomery |last18=Valle |first18=David |last19=Whittemore |first19=Alice S. |last20=Boehnke |first20=Michael |last21=Clark |first21=Andrew G. |last22=Eichler |first22=Evan E. |last23=Gibson |first23=Greg |last24=Haines |first24=Jonathan L. |last25=Mackay |first25=Trudy F. C. |last26=McCarroll |first26=Steven A. |last27=Visscher |first27=Peter M. |title=Finding the missing heritability of complex diseases |journal=Nature |date=October 2009 |volume=461 |issue=7265 |pages=747–753 |doi=10.1038/nature08494|pmid=19812666 |pmc=2831613 |bibcode=2009Natur.461..747M }}</ref> [[rare functional variant|Rare variants]] may account for some of the [[missing heritability]].<ref>{{cite journal |last1=Wainschtein |first1=Pierrick |last2=Jain |first2=Deepti |last3=Zheng |first3=Zhili |last4=Aslibekyan |first4=Stella |last5=Becker |first5=Diane |last6=Bi |first6=Wenjian |last7=Brody |first7=Jennifer |last8=Carlson |first8=Jenna C. |last9=Correa |first9=Adolfo |last10=Du |first10=Margaret Mengmeng |last11=Fernandez-Rhodes |first11=Lindsay |last12=Ferrier |first12=Kendra R. |last13=Graff |first13=Misa |last14=Guo |first14=Xiuqing |last15=He |first15=Jiang |last16=Heard-Costa |first16=Nancy L. |last17=Highland |first17=Heather M. |last18=Hirschhorn |first18=Joel N. |last19=Howard-Claudio |first19=Candace M. |last20=Isasi |first20=Carmen R. |last21=Jackson |first21=Rebecca |last22=Jiang |first22=Jicai |last23=Joehanes |first23=Roby |last24=Justice |first24=Anne E. |last25=Kalyani |first25=Rita R. |last26=Kardia |first26=Sharon |last27=Lange |first27=Ethan |last28=LeBoff |first28=Meryl |last29=Lee |first29=Seunggeun |last30=Li |first30=Xihao |last31=Li |first31=Zilin |last32=Lim |first32=Elise |last33=Lin |first33=Danyu |last34=Lin |first34=Xihong |last35=Liu |first35=Simin |last36=Lu |first36=Yingchang |last37=Manson |first37=JoAnn |last38=Martin |first38=Lisa |last39=McHugh |first39=Caitlin |last40=Mikulla |first40=Julie |last41=Musani |first41=Solomon K. |last42=Ng |first42=Maggie |last43=Nickerson |first43=Deborah |last44=Palmer |first44=Nicholette |last45=Perry |first45=James |last46=Peters |first46=Ulrike |last47=Preuss |first47=Michael |last48=Qi |first48=Qibin |last49=Raffield |first49=Laura |last50=Rasmussen-Torvik |first50=Laura |last51=Reiner |first51=Alex |last52=Russell |first52=Emily M. |last53=Sitlani |first53=Colleen |last54=Smith |first54=Jennifer |last55=Spracklen |first55=Cassandra N. |last56=Wang |first56=Tao |last57=Wang |first57=Zhe |last58=Wessel |first58=Jennifer |last59=Xu |first59=Hanfei |last60=Yaser |first60=Mohammad |last61=Yoneyama |first61=Sachiko |last62=Young |first62=Kendra A. |last63=Zhang |first63=Jingwen |last64=Zhang |first64=Xinruo |last65=Zhou |first65=Hufeng |last66=Zhu |first66=Xiaofeng |last67=Zoellner |first67=Sebastian |last68=Abe |first68=Namiko |last69=Abecasis |first69=Gonçalo |last70=Aguet |first70=Francois |last71=Almasy |first71=Laura |last72=Alonso |first72=Alvaro |last73=Ament |first73=Seth |last74=Anderson |first74=Peter |last75=Anugu |first75=Pramod |last76=Applebaum-Bowden |first76=Deborah |last77=Ardlie |first77=Kristin |last78=Arking |first78=Dan |last79=Ashley-Koch |first79=Allison |last80=Assimes |first80=Tim |last81=Auer |first81=Paul |last82=Avramopoulos |first82=Dimitrios |last83=Ayas |first83=Najib |last84=Balasubramanian |first84=Adithya |last85=Barnard |first85=John |last86=Barnes |first86=Kathleen |last87=Barr |first87=R. Graham |last88=Barron-Casella |first88=Emily |last89=Barwick |first89=Lucas |last90=Beaty |first90=Terri |last91=Beck |first91=Gerald |last92=Becker |first92=Lewis |last93=Beer |first93=Rebecca |last94=Beitelshees |first94=Amber |last95=Benjamin |first95=Emelia |last96=Benos |first96=Takis |last97=Bezerra |first97=Marcos |last98=Bielak |first98=Larry |last99=Bis |first99=Joshua |last100=Blackwell |first100=Thomas |last101=Blangero |first101=John |last102=Bowden |first102=Donald W. |last103=Bowler |first103=Russell |last104=Broeckel |first104=Ulrich |last105=Broome |first105=Jai |last106=Brown |first106=Deborah |last107=Bunting |first107=Karen |last108=Burchard |first108=Esteban |last109=Bustamante |first109=Carlos |last110=Buth |first110=Erin |last111=Cade |first111=Brian |last112=Cardwell |first112=Jonathan |last113=Carey |first113=Vincent |last114=Carrier |first114=Julie |last115=Carson |first115=April |last116=Carty |first116=Cara |last117=Casaburi |first117=Richard |last118=Romero |first118=Juan P. Casas |last119=Casella |first119=James |last120=Castaldi |first120=Peter |last121=Chaffin |first121=Mark |last122=Chang |first122=Christy |last123=Chang |first123=Yi-Cheng |last124=Chavan |first124=Sameer |last125=Chen |first125=Bo-Juen |last126=Chen |first126=Wei-Min |last127=Cho |first127=Michael |last128=Choi |first128=Seung Hoan |last129=Chuang |first129=Lee-Ming |last130=Chung |first130=Ren-Hua |last131=Clish |first131=Clary |last132=Comhair |first132=Suzy |last133=Conomos |first133=Matthew |last134=Cornell |first134=Elaine |last135=Crandall |first135=Carolyn |last136=Crapo |first136=James |last137=Curran |first137=Joanne |last138=Curtis |first138=Jeffrey |last139=Custer |first139=Brian |last140=Damcott |first140=Coleen |last141=Darbar |first141=Dawood |last142=David |first142=Sean |last143=Davis |first143=Colleen |last144=Daya |first144=Michelle |last145=de las Fuentes |first145=Lisa |last146=de Vries |first146=Paul |last147=DeBaun |first147=Michael |last148=Deka |first148=Ranjan |last149=DeMeo |first149=Dawn |last150=Devine |first150=Scott |last151=Dinh |first151=Huyen |last152=Doddapaneni |first152=Harsha |last153=Duan |first153=Qing |last154=Dugan-Perez |first154=Shannon |last155=Duggirala |first155=Ravi |last156=Durda |first156=Jon Peter |last157=Dutcher |first157=Susan K. |last158=Eaton |first158=Charles |last159=Ekunwe |first159=Lynette |last160=El Boueiz |first160=Adel |last161=Emery |first161=Leslie |last162=Erzurum |first162=Serpil |last163=Farber |first163=Charles |last164=Farek |first164=Jesse |last165=Fingerlin |first165=Tasha |last166=Flickinger |first166=Matthew |last167=Franceschini |first167=Nora |last168=Frazar |first168=Chris |last169=Fu |first169=Mao |last170=Fullerton |first170=Stephanie M. |last171=Fulton |first171=Lucinda |last172=Gabriel |first172=Stacey |last173=Gan |first173=Weiniu |last174=Gao |first174=Shanshan |last175=Gao |first175=Yan |last176=Gass |first176=Margery |last177=Geiger |first177=Heather |last178=Gelb |first178=Bruce |last179=Geraci |first179=Mark |last180=Germer |first180=Soren |last181=Gerszten |first181=Robert |last182=Ghosh |first182=Auyon |last183=Gibbs |first183=Richard |last184=Gignoux |first184=Chris |last185=Gladwin |first185=Mark |last186=Glahn |first186=David |last187=Gogarten |first187=Stephanie |last188=Gong |first188=Da-Wei |last189=Goring |first189=Harald |last190=Graw |first190=Sharon |last191=Gray |first191=Kathryn J. |last192=Grine |first192=Daniel |last193=Gross |first193=Colin |last194=Gu |first194=C. Charles |last195=Guan |first195=Yue |last196=Gupta |first196=Namrata |last197=Haas |first197=David M. |last198=Haessler |first198=Jeff |last199=Hall |first199=Michael |last200=Han |first200=Yi |last201=Hanly |first201=Patrick |last202=Harris |first202=Daniel |last203=Hawley |first203=Nicola L. |last204=Heavner |first204=Ben |last205=Herrington |first205=David |last206=Hersh |first206=Craig |last207=Hidalgo |first207=Bertha |last208=Hixson |first208=James |last209=Hobbs |first209=Brian |last210=Hokanson |first210=John |last211=Hong |first211=Elliott |last212=Hoth |first212=Karin |last213=Hsiung |first213=Chao Agnes |last214=Hu |first214=Jianhong |last215=Hung |first215=Yi-Jen |last216=Huston |first216=Haley |last217=Hwu |first217=Chii Min |last218=Irvin |first218=Marguerite Ryan |last219=Jaquish |first219=Cashell |last220=Johnsen |first220=Jill |last221=Johnson |first221=Andrew |last222=Johnson |first222=Craig |last223=Johnston |first223=Rich |last224=Jones |first224=Kimberly |last225=Kang |first225=Hyun Min |last226=Kaplan |first226=Robert |last227=Kelly |first227=Shannon |last228=Kenny |first228=Eimear |last229=Kessler |first229=Michael |last230=Khan |first230=Alyna |last231=Khan |first231=Ziad |last232=Kim |first232=Wonji |last233=Kimoff |first233=John |last234=Kinney |first234=Greg |last235=Konkle |first235=Barbara |last236=Kramer |first236=Holly |last237=Lange |first237=Christoph |last238=Lee |first238=Jiwon |last239=Lee |first239=Sandra |last240=Lee |first240=Wen-Jane |last241=LeFaive |first241=Jonathon |last242=Levine |first242=David |last243=Levy |first243=Dan |last244=Lewis |first244=Joshua |last245=Li |first245=Xiaohui |last246=Li |first246=Yun |last247=Lin |first247=Henry |last248=Lin |first248=Honghuang |last249=Liu |first249=Yongmei |last250=Liu |first250=Yu |last251=Lunetta |first251=Kathryn |last252=Luo |first252=James |last253=Magalang |first253=Ulysses |last254=Mahaney |first254=Michael |last255=Make |first255=Barry |last256=Manichaikul |first256=Ani |last257=Manning |first257=Alisa |last258=Marton |first258=Melissa |last259=Mathai |first259=Susan |last260=May |first260=Susanne |last261=McArdle |first261=Patrick |last262=McFarland |first262=Sean |last263=McGoldrick |first263=Daniel |last264=McNeil |first264=Becky |last265=Mei |first265=Hao |last266=Meigs |first266=James |last267=Menon |first267=Vipin |last268=Mestroni |first268=Luisa |last269=Metcalf |first269=Ginger |last270=Meyers |first270=Deborah A. |last271=Mignot |first271=Emmanuel |last272=Mikulla |first272=Julie |last273=Min |first273=Nancy |last274=Minear |first274=Mollie |last275=Minster |first275=Ryan L. |last276=Moll |first276=Matt |last277=Momin |first277=Zeineen |last278=Montasser |first278=May E. |last279=Montgomery |first279=Courtney |last280=Muzny |first280=Donna |last281=Mychaleckyj |first281=Josyf C. |last282=Nadkarni |first282=Girish |last283=Naik |first283=Rakhi |last284=Naseri |first284=Take |last285=Natarajan |first285=Pradeep |last286=Nekhai |first286=Sergei |last287=Nelson |first287=Sarah C. |last288=Neltner |first288=Bonnie |last289=Nessner |first289=Caitlin |last290=Nkechinyere |first290=Osuji |last291=O'Connor |first291=Tim |last292=Ochs-Balcom |first292=Heather |last293=Okwuonu |first293=Geoffrey |last294=Pack |first294=Allan |last295=Paik |first295=David T. |last296=Palmer |first296=Nicholette |last297=Pankow |first297=James |last298=Papanicolaou |first298=George |last299=Parker |first299=Cora |last300=Peloso |first300=Gina |last301=Peralta |first301=Juan Manuel |last302=Perez |first302=Marco |last303=Peyser |first303=Patricia |last304=Phillips |first304=Lawrence S. |last305=Pleiness |first305=Jacob |last306=Pollin |first306=Toni |last307=Post |first307=Wendy |last308=Becker |first308=Julia Powers |last309=Boorgula |first309=Meher Preethi |last310=Qasba |first310=Pankaj |last311=Qiao |first311=Dandi |last312=Qin |first312=Zhaohui |last313=Rafaels |first313=Nicholas |last314=Rajendran |first314=Mahitha |last315=Rao |first315=D. C. |last316=Ratan |first316=Aakrosh |last317=Reed |first317=Robert |last318=Reeves |first318=Catherine |last319=Reupena |first319=Muagututi'a Sefuiva |last320=Rice |first320=Ken |last321=Robillard |first321=Rebecca |last322=Robine |first322=Nicolas |last323=Roselli |first323=Carolina |last324=Ruczinski |first324=Ingo |last325=Runnels |first325=Alexi |last326=Russell |first326=Pamela |last327=Ruuska |first327=Sarah |last328=Ryan |first328=Kathleen |last329=Sabino |first329=Ester Cerdeira |last330=Saleheen |first330=Danish |last331=Salimi |first331=Shabnam |last332=Salvi |first332=Sejal |last333=Salzberg |first333=Steven |last334=Sandow |first334=Kevin |last335=Sankaran |first335=Vijay G. |last336=Santibanez |first336=Jireh |last337=Schwander |first337=Karen |last338=Schwartz |first338=David |last339=Sciurba |first339=Frank |last340=Seidman |first340=Christine |last341=Seidman |first341=Jonathan |last342=Sheehan |first342=Vivien |last343=Sherman |first343=Stephanie L. |last344=Shetty |first344=Amol |last345=Shetty |first345=Aniket |last346=Sheu |first346=Wayne Hui-Heng |last347=Silver |first347=Brian |last348=Silverman |first348=Edwin |last349=Skomro |first349=Robert |last350=Smith |first350=Albert Vernon |last351=Smith |first351=Josh |last352=Smith |first352=Tanja |last353=Smoller |first353=Sylvia |last354=Snively |first354=Beverly |last355=Snyder |first355=Michael |last356=Sofer |first356=Tamar |last357=Sotoodehnia |first357=Nona |last358=Stilp |first358=Adrienne M. |last359=Storm |first359=Garrett |last360=Streeten |first360=Elizabeth |last361=Su |first361=Jessica Lasky |last362=Sung |first362=Yun Ju |last363=Sylvia |first363=Jody |last364=Szpiro |first364=Adam |last365=Taliun |first365=Daniel |last366=Tang |first366=Hua |last367=Taub |first367=Margaret |last368=Taylor |first368=Kent D. |last369=Taylor |first369=Matthew |last370=Taylor |first370=Simeon |last371=Telen |first371=Marilyn |last372=Thornton |first372=Timothy A. |last373=Threlkeld |first373=Machiko |last374=Tinker |first374=Lesley |last375=Tirschwell |first375=David |last376=Tishkoff |first376=Sarah |last377=Tiwari |first377=Hemant |last378=Tong |first378=Catherine |last379=Tracy |first379=Russell |last380=Tsai |first380=Michael |last381=Vaidya |first381=Dhananjay |last382=Van Den Berg |first382=David |last383=VandeHaar |first383=Peter |last384=Vrieze |first384=Scott |last385=Walker |first385=Tarik |last386=Wallace |first386=Robert |last387=Walts |first387=Avram |last388=Wang |first388=Fei Fei |last389=Wang |first389=Heming |last390=Wang |first390=Jiongming |last391=Watson |first391=Karol |last392=Watt |first392=Jennifer |last393=Weeks |first393=Daniel E. |last394=Weinstock |first394=Joshua |last395=Weiss |first395=Scott T. |last396=Weng |first396=Lu-Chen |last397=Willer |first397=Cristen |last398=Williams |first398=Kayleen |last399=Williams |first399=L. Keoki |last400=Wilson |first400=Carla |last401=Wilson |first401=James |last402=Winterkorn |first402=Lara |last403=Wong |first403=Quenna |last404=Wu |first404=Joseph |last405=Xu |first405=Huichun |last406=Yang |first406=Ivana |last407=Yu |first407=Ketian |last408=Zekavat |first408=Seyedeh Maryam |last409=Zhang |first409=Yingze |last410=Zhao |first410=Snow Xueyan |last411=Zhao |first411=Wei |last412=Zody |first412=Michael |last413=Cupples |first413=L. Adrienne |last414=Shadyab |first414=Aladdin H. |last415=McKnight |first415=Barbara |last416=Shoemaker |first416=Benjamin M. |last417=Mitchell |first417=Braxton D. |last418=Psaty |first418=Bruce M. |last419=Kooperberg |first419=Charles |last420=Liu |first420=Ching-Ti |last421=Albert |first421=Christine M. |last422=Roden |first422=Dan |last423=Chasman |first423=Daniel I. |last424=Darbar |first424=Dawood |last425=Lloyd-Jones |first425=Donald M. |last426=Arnett |first426=Donna K. |last427=Regan |first427=Elizabeth A. |last428=Boerwinkle |first428=Eric |last429=Rotter |first429=Jerome I. |last430=O'Connell |first430=Jeffrey R. |last431=Yanek |first431=Lisa R. |last432=de Andrade |first432=Mariza |last433=Allison |first433=Matthew A. |last434=McDonald |first434=Merry-Lynn N. |last435=Chung |first435=Mina K. |last436=Fornage |first436=Myriam |last437=Chami |first437=Nathalie |last438=Smith |first438=Nicholas L. |last439=Ellinor |first439=Patrick T. |last440=Vasan |first440=Ramachandran S. |last441=Mathias |first441=Rasika A. |last442=Loos |first442=Ruth J. F. |last443=Rich |first443=Stephen S. |last444=Lubitz |first444=Steven A. |last445=Heckbert |first445=Susan R. |last446=Redline |first446=Susan |last447=Guo |first447=Xiuqing |last448=Chen |first448=Y. -D Ida |last449=Laurie |first449=Cecelia A. |last450=Hernandez |first450=Ryan D. |last451=McGarvey |first451=Stephen T. |last452=Goddard |first452=Michael E. |last453=Laurie |first453=Cathy C. |last454=North |first454=Kari E. |last455=Lange |first455=Leslie A. |last456=Weir |first456=Bruce S. |last457=Yengo |first457=Loic |last458=Yang |first458=Jian |last459=Visscher |first459=Peter M.|title=Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data |journal=Nature Genetics |date=March 2022 |volume=54 |issue=3 |pages=263–273 |doi=10.1038/s41588-021-00997-7|pmid=35256806 |pmc=9119698 }}</ref> Large-scale [[whole genome sequencing]] studies have rapidly sequenced millions of whole genomes, and such studies have identified hundreds of millions of [[rare functional variant|rare variants]].<ref>{{cite journal |last1=Taliun |first1=Daniel |last2=Harris |first2=Daniel N. |last3=Kessler |first3=Michael D. |last4=Carlson |first4=Jedidiah |last5=Szpiech |first5=Zachary A. |last6=Torres |first6=Raul |last7=Taliun |first7=Sarah A. Gagliano |last8=Corvelo |first8=André |last9=Gogarten |first9=Stephanie M. |last10=Kang |first10=Hyun Min |last11=Pitsillides |first11=Achilleas N. |last12=LeFaive |first12=Jonathon |last13=Lee |first13=Seung-been |last14=Tian |first14=Xiaowen |last15=Browning |first15=Brian L. |last16=Das |first16=Sayantan |last17=Emde |first17=Anne-Katrin |last18=Clarke |first18=Wayne E. |last19=Loesch |first19=Douglas P. |last20=Shetty |first20=Amol C. |last21=Blackwell |first21=Thomas W. |last22=Smith |first22=Albert V. |last23=Wong |first23=Quenna |last24=Liu |first24=Xiaoming |last25=Conomos |first25=Matthew P. |last26=Bobo |first26=Dean M. |last27=Aguet |first27=François |last28=Albert |first28=Christine |last29=Alonso |first29=Alvaro |last30=Ardlie |first30=Kristin G. |last31=Arking |first31=Dan E. |last32=Aslibekyan |first32=Stella |last33=Auer |first33=Paul L. |last34=Barnard |first34=John |last35=Barr |first35=R. Graham |last36=Barwick |first36=Lucas |last37=Becker |first37=Lewis C. |last38=Beer |first38=Rebecca L. |last39=Benjamin |first39=Emelia J. |last40=Bielak |first40=Lawrence F. |last41=Blangero |first41=John |last42=Boehnke |first42=Michael |last43=Bowden |first43=Donald W. |last44=Brody |first44=Jennifer A. |last45=Burchard |first45=Esteban G. |last46=Cade |first46=Brian E. |last47=Casella |first47=James F. |last48=Chalazan |first48=Brandon |last49=Chasman |first49=Daniel I. |last50=Chen |first50=Yii-Der Ida |last51=Cho |first51=Michael H. |last52=Choi |first52=Seung Hoan |last53=Chung |first53=Mina K. |last54=Clish |first54=Clary B. |last55=Correa |first55=Adolfo |last56=Curran |first56=Joanne E. |last57=Custer |first57=Brian |last58=Darbar |first58=Dawood |last59=Daya |first59=Michelle |last60=de Andrade |first60=Mariza |last61=DeMeo |first61=Dawn L. |last62=Dutcher |first62=Susan K. |last63=Ellinor |first63=Patrick T. |last64=Emery |first64=Leslie S. |last65=Eng |first65=Celeste |last66=Fatkin |first66=Diane |last67=Fingerlin |first67=Tasha |last68=Forer |first68=Lukas |last69=Fornage |first69=Myriam |last70=Franceschini |first70=Nora |last71=Fuchsberger |first71=Christian |last72=Fullerton |first72=Stephanie M. |last73=Germer |first73=Soren |last74=Gladwin |first74=Mark T. |last75=Gottlieb |first75=Daniel J. |last76=Guo |first76=Xiuqing |last77=Hall |first77=Michael E. |last78=He |first78=Jiang |last79=Heard-Costa |first79=Nancy L. |last80=Heckbert |first80=Susan R. |last81=Irvin |first81=Marguerite R. |last82=Johnsen |first82=Jill M. |last83=Johnson |first83=Andrew D. |last84=Kaplan |first84=Robert |last85=Kardia |first85=Sharon L. R. |last86=Kelly |first86=Tanika |last87=Kelly |first87=Shannon |last88=Kenny |first88=Eimear E. |last89=Kiel |first89=Douglas P. |last90=Klemmer |first90=Robert |last91=Konkle |first91=Barbara A. |last92=Kooperberg |first92=Charles |last93=Köttgen |first93=Anna |last94=Lange |first94=Leslie A. |last95=Lasky-Su |first95=Jessica |last96=Levy |first96=Daniel |last97=Lin |first97=Xihong |last98=Lin |first98=Keng-Han |last99=Liu |first99=Chunyu  |display-authors=1 |last100=Loos |first100=Ruth J. F. |last101=Garman |first101=Lori |last102=Gerszten |first102=Robert |last103=Lubitz |first103=Steven A. |last104=Lunetta |first104=Kathryn L. |last105=Mak |first105=Angel C. Y. |last106=Manichaikul |first106=Ani |last107=Manning |first107=Alisa K. |last108=Mathias |first108=Rasika A. |last109=McManus |first109=David D. |last110=McGarvey |first110=Stephen T. |last111=Meigs |first111=James B. |last112=Meyers |first112=Deborah A. |last113=Mikulla |first113=Julie L. |last114=Minear |first114=Mollie A. |last115=Mitchell |first115=Braxton D. |last116=Mohanty |first116=Sanghamitra |last117=Montasser |first117=May E. |last118=Montgomery |first118=Courtney |last119=Morrison |first119=Alanna C. |last120=Murabito |first120=Joanne M. |last121=Natale |first121=Andrea |last122=Natarajan |first122=Pradeep |last123=Nelson |first123=Sarah C. |last124=North |first124=Kari E. |last125=O'Connell |first125=Jeffrey R. |last126=Palmer |first126=Nicholette D. |last127=Pankratz |first127=Nathan |last128=Peloso |first128=Gina M. |last129=Peyser |first129=Patricia A. |last130=Pleiness |first130=Jacob |last131=Post |first131=Wendy S. |last132=Psaty |first132=Bruce M. |last133=Rao |first133=D. C. |last134=Redline |first134=Susan |last135=Reiner |first135=Alexander P. |last136=Roden |first136=Dan |last137=Rotter |first137=Jerome I. |last138=Ruczinski |first138=Ingo |last139=Sarnowski |first139=Chloé |last140=Schoenherr |first140=Sebastian |last141=Schwartz |first141=David A. |last142=Seo |first142=Jeong-Sun |last143=Seshadri |first143=Sudha |last144=Sheehan |first144=Vivien A. |last145=Sheu |first145=Wayne H. |last146=Shoemaker |first146=M. Benjamin |last147=Smith |first147=Nicholas L. |last148=Smith |first148=Jennifer A. |last149=Sotoodehnia |first149=Nona |last150=Stilp |first150=Adrienne M. |last151=Tang |first151=Weihong |last152=Taylor |first152=Kent D. |last153=Telen |first153=Marilyn |last154=Thornton |first154=Timothy A. |last155=Tracy |first155=Russell P. |last156=Van Den Berg |first156=David J. |last157=Vasan |first157=Ramachandran S. |last158=Viaud-Martinez |first158=Karine A. |last159=Vrieze |first159=Scott |last160=Weeks |first160=Daniel E. |last161=Weir |first161=Bruce S. |last162=Weiss |first162=Scott T. |last163=Weng |first163=Lu-Chen |last164=Willer |first164=Cristen J. |last165=Zhang |first165=Yingze |last166=Zhao |first166=Xutong |last167=Arnett |first167=Donna K. |last168=Ashley-Koch |first168=Allison E. |last169=Barnes |first169=Kathleen C. |last170=Boerwinkle |first170=Eric |last171=Gabriel |first171=Stacey |last172=Gibbs |first172=Richard |last173=Rice |first173=Kenneth M. |last174=Rich |first174=Stephen S. |last175=Silverman |first175=Edwin K. |last176=Qasba |first176=Pankaj |last177=Gan |first177=Weiniu |last178=Papanicolaou |first178=George J. |last179=Nickerson |first179=Deborah A. |last180=Browning |first180=Sharon R. |last181=Zody |first181=Michael C. |last182=Zöllner |first182=Sebastian |last183=Wilson |first183=James G. |last184=Cupples |first184=L. Adrienne |last185=Laurie |first185=Cathy C. |last186=Jaquish |first186=Cashell E. |last187=Hernandez |first187=Ryan D. |last188=O'Connor |first188=Timothy D. |last189=Abecasis |first189=Gonçalo R. |title=Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program |journal=Nature |date=February 2021 |volume=590 |issue=7845 |pages=290–299 |doi=10.1038/s41586-021-03205-y|pmid=33568819 |pmc=7875770 |bibcode=2021Natur.590..290T }}</ref> [[SNP annotation|Functional annotations]] predict the effect or function of a genetic variant and help to prioritize rare functional variants, and incorporating these annotations can effectively boost the power of genetic association of rare variants analysis of whole genome sequencing studies.<ref>{{cite journal |last1=Li |first1=Xihao |last2=Li |first2=Zilin |last3=Zhou |first3=Hufeng |last4=Gaynor |first4=Sheila M. |last5=Liu |first5=Yaowu |last6=Chen |first6=Han |last7=Sun |first7=Ryan |last8=Dey |first8=Rounak |last9=Arnett |first9=Donna K. |last10=Aslibekyan |first10=Stella |last11=Ballantyne |first11=Christie M. |last12=Bielak |first12=Lawrence F. |last13=Blangero |first13=John |last14=Boerwinkle |first14=Eric |last15=Bowden |first15=Donald W. |last16=Broome |first16=Jai G. |last17=Conomos |first17=Matthew P. |last18=Correa |first18=Adolfo |last19=Cupples |first19=L. Adrienne |last20=Curran |first20=Joanne E. |last21=Freedman |first21=Barry I. |last22=Guo |first22=Xiuqing |last23=Hindy |first23=George |last24=Irvin |first24=Marguerite R. |last25=Kardia |first25=Sharon L. R. |last26=Kathiresan |first26=Sekar |last27=Khan |first27=Alyna T. |last28=Kooperberg |first28=Charles L. |last29=Laurie |first29=Cathy C. |last30=Liu |first30=X. Shirley |last31=Mahaney |first31=Michael C. |last32=Manichaikul |first32=Ani W. |last33=Martin |first33=Lisa W. |last34=Mathias |first34=Rasika A. |last35=McGarvey |first35=Stephen T. |last36=Mitchell |first36=Braxton D. |last37=Montasser |first37=May E. |last38=Moore |first38=Jill E. |last39=Morrison |first39=Alanna C. |last40=O'Connell |first40=Jeffrey R. |last41=Palmer |first41=Nicholette D. |last42=Pampana |first42=Akhil |last43=Peralta |first43=Juan M. |last44=Peyser |first44=Patricia A. |last45=Psaty |first45=Bruce M. |last46=Redline |first46=Susan |last47=Rice |first47=Kenneth M. |last48=Rich |first48=Stephen S. |last49=Smith |first49=Jennifer A. |last50=Tiwari |first50=Hemant K. |last51=Tsai |first51=Michael Y. |last52=Vasan |first52=Ramachandran S. |last53=Wang |first53=Fei Fei |last54=Weeks |first54=Daniel E. |last55=Weng |first55=Zhiping |last56=Wilson |first56=James G. |last57=Yanek |first57=Lisa R. |last58=Abe |first58=Namiko |last59=Abecasis |first59=Gonçalo R. |last60=Aguet |first60=Francois |last61=Albert |first61=Christine |last62=Almasy |first62=Laura |last63=Alonso |first63=Alvaro |last64=Ament |first64=Seth |last65=Anderson |first65=Peter |last66=Anugu |first66=Pramod |last67=Applebaum-Bowden |first67=Deborah |last68=Ardlie |first68=Kristin |last69=Arking |first69=Dan |last70=Arnett |first70=Donna K. |last71=Ashley-Koch |first71=Allison |last72=Aslibekyan |first72=Stella |last73=Assimes |first73=Tim |last74=Auer |first74=Paul |last75=Avramopoulos |first75=Dimitrios |last76=Barnard |first76=John |last77=Barnes |first77=Kathleen |last78=Barr |first78=R. Graham |last79=Barron-Casella |first79=Emily |last80=Barwick |first80=Lucas |last81=Beaty |first81=Terri |last82=Beck |first82=Gerald |last83=Becker |first83=Diane |last84=Becker |first84=Lewis |last85=Beer |first85=Rebecca |last86=Beitelshees |first86=Amber |last87=Benjamin |first87=Emelia |last88=Benos |first88=Takis |last89=Bezerra |first89=Marcos |last90=Bielak |first90=Lawrence F. |last91=Bis |first91=Joshua |last92=Blackwell |first92=Thomas |last93=Blangero |first93=John |last94=Boerwinkle |first94=Eric |last95=Bowden |first95=Donald W. |last96=Bowler |first96=Russell |last97=Brody |first97=Jennifer |last98=Broeckel |first98=Ulrich |last99=Broome |first99=Jai G. |last100=Bunting |first100=Karen |last101=Burchard |first101=Esteban |last102=Bustamante |first102=Carlos |last103=Buth |first103=Erin |last104=Cade |first104=Brian |last105=Cardwell |first105=Jonathan |last106=Carey |first106=Vincent |last107=Carty |first107=Cara |last108=Casaburi |first108=Richard |last109=Casella |first109=James |last110=Castaldi |first110=Peter |last111=Chaffin |first111=Mark |last112=Chang |first112=Christy |last113=Chang |first113=Yi-Cheng |last114=Chasman |first114=Daniel |last115=Chavan |first115=Sameer |last116=Chen |first116=Bo-Juen |last117=Chen |first117=Wei-Min |last118=Chen |first118=Yii-Der Ida |last119=Cho |first119=Michael |last120=Choi |first120=Seung Hoan |last121=Chuang |first121=Lee-Ming |last122=Chung |first122=Mina |last123=Chung |first123=Ren-Hua |last124=Clish |first124=Clary |last125=Comhair |first125=Suzy |last126=Conomos |first126=Matthew P. |last127=Cornell |first127=Elaine |last128=Correa |first128=Adolfo |last129=Crandall |first129=Carolyn |last130=Crapo |first130=James |last131=Cupples |first131=L. Adrienne |last132=Curran |first132=Joanne E. |last133=Curtis |first133=Jeffrey |last134=Custer |first134=Brian |last135=Damcott |first135=Coleen |last136=Darbar |first136=Dawood |last137=Das |first137=Sayantan |last138=David |first138=Sean |last139=Davis |first139=Colleen |last140=Daya |first140=Michelle |last141=de Andrade |first141=Mariza |last142=Fuentes |first142=Lisa de las |last143=DeBaun |first143=Michael |last144=Deka |first144=Ranjan |last145=DeMeo |first145=Dawn |last146=Devine |first146=Scott |last147=Duan |first147=Qing |last148=Duggirala |first148=Ravi |last149=Durda |first149=Jon Peter |last150=Dutcher |first150=Susan |last151=Eaton |first151=Charles |last152=Ekunwe |first152=Lynette |last153=El Boueiz |first153=Adel |last154=Ellinor |first154=Patrick |last155=Emery |first155=Leslie |last156=Erzurum |first156=Serpil |last157=Farber |first157=Charles |last158=Fingerlin |first158=Tasha |last159=Flickinger |first159=Matthew |last160=Fornage |first160=Myriam |last161=Franceschini |first161=Nora |last162=Frazar |first162=Chris |last163=Fu |first163=Mao |last164=Fullerton |first164=Stephanie M. |last165=Fulton |first165=Lucinda |last166=Gabriel |first166=Stacey |last167=Gan |first167=Weiniu |last168=Gao |first168=Shanshan |last169=Gao |first169=Yan |last170=Gass |first170=Margery |last171=Gelb |first171=Bruce |last172=Geng |first172=Xiaoqi |last173=Geraci |first173=Mark |last174=Germer |first174=Soren |last175=Gerszten |first175=Robert |last176=Ghosh |first176=Auyon |last177=Gibbs |first177=Richard |last178=Gignoux |first178=Chris |last179=Gladwin |first179=Mark |last180=Glahn |first180=David |last181=Gogarten |first181=Stephanie |last182=Gong |first182=Da-Wei |last183=Goring |first183=Harald |last184=Graw |first184=Sharon |last185=Grine |first185=Daniel |last186=Gu |first186=C. Charles |last187=Guan |first187=Yue |last188=Guo |first188=Xiuqing |last189=Gupta |first189=Namrata |last190=Haessler |first190=Jeff |last191=Hall |first191=Michael |last192=Harris |first192=Daniel |last193=Hawley |first193=Nicola L. |last194=He |first194=Jiang |last195=Heckbert |first195=Susan |last196=Hernandez |first196=Ryan |last197=Herrington |first197=David |last198=Hersh |first198=Craig |last199=Hidalgo |first199=Bertha |last200=Hixson |first200=James |last201=Hobbs |first201=Brian |last202=Hokanson |first202=John |last203=Hong |first203=Elliott |last204=Hoth |first204=Karin |last205=Hsiung |first205=Chao |last206=Hung |first206=Yi-Jen |last207=Huston |first207=Haley |last208=Hwu |first208=Chii Min |last209=Irvin |first209=Marguerite R. |last210=Jackson |first210=Rebecca |last211=Jain |first211=Deepti |last212=Jaquish |first212=Cashell |last213=Jhun |first213=Min A. |last214=Johnsen |first214=Jill |last215=Johnson |first215=Andrew |last216=Johnson |first216=Craig |last217=Johnston |first217=Rich |last218=Jones |first218=Kimberly |last219=Kang |first219=Hyun Min |last220=Kaplan |first220=Robert |last221=Kardia |first221=Sharon L. R. |last222=Kathiresan |first222=Sekar |last223=Kelly |first223=Shannon |last224=Kenny |first224=Eimear |last225=Kessler |first225=Michael |last226=Khan |first226=Alyna T. |last227=Kim |first227=Wonji |last228=Kinney |first228=Greg |last229=Konkle |first229=Barbara |last230=Kooperberg |first230=Charles L. |last231=Kramer |first231=Holly |last232=Lange |first232=Christoph |last233=Lange |first233=Ethan |last234=Lange |first234=Leslie |last235=Laurie |first235=Cathy C. |last236=Laurie |first236=Cecelia |last237=LeBoff |first237=Meryl |last238=Lee |first238=Jiwon |last239=Lee |first239=Seunggeun Shawn |last240=Lee |first240=Wen-Jane |last241=LeFaive |first241=Jonathon |last242=Levine |first242=David |last243=Levy |first243=Dan |last244=Lewis |first244=Joshua |last245=Li |first245=Xiaohui |last246=Li |first246=Yun |last247=Lin |first247=Henry |last248=Lin |first248=Honghuang |last249=Lin |first249=Keng Han |last250=Lin |first250=Xihong |last251=Liu |first251=Simin |last252=Liu |first252=Yongmei |last253=Liu |first253=Yu |last254=Loos |first254=Ruth J. F. |last255=Lubitz |first255=Steven |last256=Lunetta |first256=Kathryn |last257=Luo |first257=James |last258=Mahaney |first258=Michael C. |last259=Make |first259=Barry |last260=Manichaikul |first260=Ani W. |last261=Manson |first261=JoAnn |last262=Margolin |first262=Lauren |last263=Martin |first263=Lisa W. |last264=Mathai |first264=Susan |last265=Mathias |first265=Rasika A. |last266=May |first266=Susanne |last267=McArdle |first267=Patrick |last268=McDonald |first268=Merry-Lynn |last269=McFarland |first269=Sean |last270=McGarvey |first270=Stephen T. |last271=McGoldrick |first271=Daniel |last272=McHugh |first272=Caitlin |last273=Mei |first273=Hao |last274=Mestroni |first274=Luisa |last275=Meyers |first275=Deborah A. |last276=Mikulla |first276=Julie |last277=Min |first277=Nancy |last278=Minear |first278=Mollie |last279=Minster |first279=Ryan L. |last280=Mitchell |first280=Braxton D. |last281=Moll |first281=Matt |last282=Montasser |first282=May E. |last283=Montgomery |first283=Courtney |last284=Moscati |first284=Arden |last285=Musani |first285=Solomon |last286=Mwasongwe |first286=Stanford |last287=Mychaleckyj |first287=Josyf C. |last288=Nadkarni |first288=Girish |last289=Naik |first289=Rakhi |last290=Naseri |first290=Take |last291=Natarajan |first291=Pradeep |last292=Nekhai |first292=Sergei |last293=Nelson |first293=Sarah C. |last294=Neltner |first294=Bonnie |last295=Nickerson |first295=Deborah |last296=North |first296=Kari |last297=O'Connell |first297=Jeffrey R. |last298=O'Connor |first298=Tim |last299=Ochs-Balcom |first299=Heather |last300=Paik |first300=David |last301=Palmer |first301=Nicholette D. |last302=Pankow |first302=James |last303=Papanicolaou |first303=George |last304=Parsa |first304=Afshin |last305=Peralta |first305=Juan M. |last306=Perez |first306=Marco |last307=Perry |first307=James |last308=Peters |first308=Ulrike |last309=Peyser |first309=Patricia A. |last310=Phillips |first310=Lawrence S. |last311=Pollin |first311=Toni |last312=Post |first312=Wendy |last313=Becker |first313=Julia Powers |last314=Boorgula |first314=Meher Preethi |last315=Preuss |first315=Michael |last316=Psaty |first316=Bruce M. |last317=Qasba |first317=Pankaj |last318=Qiao |first318=Dandi |last319=Qin |first319=Zhaohui |last320=Rafaels |first320=Nicholas |last321=Raffield |first321=Laura |last322=Vasan |first322=Ramachandran S. |last323=Rao |first323=D. C. |last324=Rasmussen-Torvik |first324=Laura |last325=Ratan |first325=Aakrosh |last326=Redline |first326=Susan |last327=Reed |first327=Robert |last328=Regan |first328=Elizabeth |last329=Reiner |first329=Alex |last330=Reupena |first330=Muagututi'a Sefuiva |last331=Rice |first331=Kenneth M. |last332=Rich |first332=Stephen S. |last333=Roden |first333=Dan |last334=Roselli |first334=Carolina |last335=Rotter |first335=Jerome I. |last336=Ruczinski |first336=Ingo |last337=Russell |first337=Pamela |last338=Ruuska |first338=Sarah |last339=Ryan |first339=Kathleen |last340=Sabino |first340=Ester Cerdeira |last341=Saleheen |first341=Danish |last342=Salimi |first342=Shabnam |last343=Salzberg |first343=Steven |last344=Sandow |first344=Kevin |last345=Sankaran |first345=Vijay G. |last346=Scheller |first346=Christopher |last347=Schmidt |first347=Ellen |last348=Schwander |first348=Karen |last349=Schwartz |first349=David |last350=Sciurba |first350=Frank |last351=Seidman |first351=Christine |last352=Seidman |first352=Jonathan |last353=Sheehan |first353=Vivien |last354=Sherman |first354=Stephanie L. |last355=Shetty |first355=Amol |last356=Shetty |first356=Aniket |last357=Sheu |first357=Wayne Hui-Heng |last358=Shoemaker |first358=M. Benjamin |last359=Silver |first359=Brian |last360=Silverman |first360=Edwin |last361=Smith |first361=Jennifer A. |last362=Smith |first362=Josh |last363=Smith |first363=Nicholas |last364=Smith |first364=Tanja |last365=Smoller |first365=Sylvia |last366=Snively |first366=Beverly |last367=Snyder |first367=Michael |last368=Sofer |first368=Tamar |last369=Sotoodehnia |first369=Nona |last370=Stilp |first370=Adrienne M. |last371=Storm |first371=Garrett |last372=Streeten |first372=Elizabeth |last373=Su |first373=Jessica Lasky |last374=Sung |first374=Yun Ju |last375=Sylvia |first375=Jody |last376=Szpiro |first376=Adam |last377=Sztalryd |first377=Carole |last378=Taliun |first378=Daniel |last379=Tang |first379=Hua |last380=Taub |first380=Margaret |last381=Taylor |first381=Kent D. |last382=Taylor |first382=Matthew |last383=Taylor |first383=Simeon |last384=Telen |first384=Marilyn |last385=Thornton |first385=Timothy A. |last386=Threlkeld |first386=Machiko |last387=Tinker |first387=Lesley |last388=Tirschwell |first388=David |last389=Tishkoff |first389=Sarah |last390=Tiwari |first390=Hemant K. |last391=Tong |first391=Catherine |last392=Tracy |first392=Russell |last393=Tsai |first393=Michael Y. |last394=Vaidya |first394=Dhananjay |last395=Van Den Berg |first395=David |last396=VandeHaar |first396=Peter |last397=Vrieze |first397=Scott |last398=Walker |first398=Tarik |last399=Wallace |first399=Robert |last400=Walts |first400=Avram |last401=Wang |first401=Fei Fei |last402=Wang |first402=Heming |last403=Watson |first403=Karol |last404=Weeks |first404=Daniel E. |last405=Weir |first405=Bruce |last406=Weiss |first406=Scott |last407=Weng |first407=Lu-Chen |last408=Wessel |first408=Jennifer |last409=Willer |first409=Cristen J. |last410=Williams |first410=Kayleen |last411=Williams |first411=L. Keoki |last412=Wilson |first412=Carla |last413=Wilson |first413=James G. |last414=Wong |first414=Quenna |last415=Wu |first415=Joseph |last416=Xu |first416=Huichun |last417=Yanek |first417=Lisa R. |last418=Yang |first418=Ivana |last419=Yang |first419=Rongze |last420=Zaghloul |first420=Norann |last421=Zekavat |first421=Maryam |last422=Zhang |first422=Yingze |last423=Zhao |first423=Snow Xueyan |last424=Zhao |first424=Wei |last425=Zhi |first425=Degui |last426=Zhou |first426=Xiang |last427=Zhu |first427=Xiaofeng |last428=Zody |first428=Michael |last429=Zoellner |first429=Sebastian |last430=Abdalla |first430=Moustafa |last431=Abecasis |first431=Gonçalo R. |last432=Arnett |first432=Donna K. |last433=Aslibekyan |first433=Stella |last434=Assimes |first434=Tim |last435=Atkinson |first435=Elizabeth |last436=Ballantyne |first436=Christie M. |last437=Beitelshees |first437=Amber |last438=Bielak |first438=Lawrence F. |last439=Bis |first439=Joshua |last440=Bodea |first440=Corneliu |last441=Boerwinkle |first441=Eric |last442=Bowden |first442=Donald W. |last443=Brody |first443=Jennifer |last444=Cade |first444=Brian |last445=Carlson |first445=Jenna |last446=Chang |first446=I-Shou |last447=Chen |first447=Yii-Der Ida |last448=Chun |first448=Sung |last449=Chung |first449=Ren-Hua |last450=Conomos |first450=Matthew P. |last451=Correa |first451=Adolfo |last452=Cupples |first452=L. Adrienne |last453=Damcott |first453=Coleen |last454=de Vries |first454=Paul |last455=Do |first455=Ron |last456=Elliott |first456=Amanda |last457=Fu |first457=Mao |last458=Ganna |first458=Andrea |last459=Gong |first459=Da-Wei |last460=Graham |first460=Sarah |last461=Haas |first461=Mary |last462=Haring |first462=Bernhard |last463=He |first463=Jiang |last464=Heckbert |first464=Susan |last465=Himes |first465=Blanca |last466=Hixson |first466=James |last467=Irvin |first467=Marguerite R. |last468=Jain |first468=Deepti |last469=Jarvik |first469=Gail |last470=Jhun |first470=Min A. |last471=Jiang |first471=Jicai |last472=Jun |first472=Goo |last473=Kalyani |first473=Rita |last474=Kardia |first474=Sharon L. R. |last475=Kathiresan |first475=Sekar |last476=Khera |first476=Amit |last477=Klarin |first477=Derek |last478=Kooperberg |first478=Charles L. |last479=Kral |first479=Brian |last480=Lange |first480=Leslie |last481=Laurie |first481=Cathy C. |last482=Laurie |first482=Cecelia |last483=Lemaitre |first483=Rozenn |last484=Li |first484=Zilin |last485=Li |first485=Xihao |last486=Lin |first486=Xihong |last487=Mahaney |first487=Michael C. |last488=Manichaikul |first488=Ani W. |last489=Martin |first489=Lisa W. |last490=Mathias |first490=Rasika A. |last491=Mathur |first491=Ravi |last492=McGarvey |first492=Stephen T. |last493=McHugh |first493=Caitlin |last494=McLenithan |first494=John |last495=Mikulla |first495=Julie |last496=Mitchell |first496=Braxton D. |last497=Montasser |first497=May E. |last498=Moran |first498=Andrew |last499=Morrison |first499=Alanna C. |last500=Nakao |first500=Tetsushi |last501=Natarajan |first501=Pradeep |last502=Nickerson |first502=Deborah |last503=North |first503=Kari |last504=O'Connell |first504=Jeffrey R. |last505=O'Donnell |first505=Christopher |last506=Palmer |first506=Nicholette D. |last507=Pampana |first507=Akhil |last508=Patel |first508=Aniruddh |last509=Peloso |first509=Gina M. |last510=Perry |first510=James |last511=Peters |first511=Ulrike |last512=Peyser |first512=Patricia A. |last513=Pirruccello |first513=James |last514=Pollin |first514=Toni |last515=Preuss |first515=Michael |last516=Psaty |first516=Bruce M. |last517=Rao |first517=D. C. |last518=Redline |first518=Susan |last519=Reed |first519=Robert |last520=Reiner |first520=Alex |last521=Rich |first521=Stephen S. |last522=Rosenthal |first522=Samantha |last523=Rotter |first523=Jerome I. |last524=Schoenberg |first524=Jenny |last525=Selvaraj |first525=Margaret Sunitha |last526=Sheu |first526=Wayne Hui-Heng |last527=Smith |first527=Jennifer A. |last528=Sofer |first528=Tamar |last529=Stilp |first529=Adrienne M. |last530=Sunyaev |first530=Shamil R. |last531=Surakka |first531=Ida |last532=Sztalryd |first532=Carole |last533=Tang |first533=Hua |last534=Taylor |first534=Kent D. |last535=Tsai |first535=Michael Y. |last536=Uddin |first536=Md Mesbah |last537=Urbut |first537=Sarah |last538=Verbanck |first538=Marie |last539=Von Holle |first539=Ann |last540=Wang |first540=Heming |last541=Wang |first541=Fei Fei |last542=Wiggins |first542=Kerri |last543=Willer |first543=Cristen J. |last544=Wilson |first544=James G. |last545=Wolford |first545=Brooke |last546=Xu |first546=Huichun |last547=Yanek |first547=Lisa R. |last548=Zaghloul |first548=Norann |last549=Zekavat |first549=Maryam |last550=Zhang |first550=Jingwen |last551=Neale |first551=Benjamin M. |last552=Sunyaev |first552=Shamil R. |last553=Abecasis |first553=Gonçalo R. |last554=Rotter |first554=Jerome I. |last555=Willer |first555=Cristen J. |last556=Peloso |first556=Gina M. |last557=Natarajan |first557=Pradeep |last558=Lin |first558=Xihong|title=Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale |journal=Nature Genetics |date=September 2020 |volume=52 |issue=9 |pages=969–983 |doi=10.1038/s41588-020-0676-4|pmid=32839606 |pmc=7483769 }}</ref> Some tools have been developed to provide all-in-one rare variant association analysis for whole-genome sequencing data, including integration of genotype data and their functional annotations, association analysis, result summary and visualization.<ref>{{cite journal |last1=Li |first1=Zilin |last2=Li |first2=Xihao |last3=Zhou |first3=Hufeng |last4=Gaynor |first4=Sheila M. |last5=Selvaraj |first5=Margaret Sunitha |last6=Arapoglou |first6=Theodore |last7=Quick |first7=Corbin |last8=Liu |first8=Yaowu |last9=Chen |first9=Han |last10=Sun |first10=Ryan |last11=Dey |first11=Rounak |last12=Arnett |first12=Donna K. |last13=Auer |first13=Paul L. |last14=Bielak |first14=Lawrence F. |last15=Bis |first15=Joshua C. |last16=Blackwell |first16=Thomas W. |last17=Blangero |first17=John |last18=Boerwinkle |first18=Eric |last19=Bowden |first19=Donald W. |last20=Brody |first20=Jennifer A. |last21=Cade |first21=Brian E. |last22=Conomos |first22=Matthew P. |last23=Correa |first23=Adolfo |last24=Cupples |first24=L. Adrienne |last25=Curran |first25=Joanne E. |last26=de Vries |first26=Paul S. |last27=Duggirala |first27=Ravindranath |last28=Franceschini |first28=Nora |last29=Freedman |first29=Barry I. |last30=Göring |first30=Harald H. H. |last31=Guo |first31=Xiuqing |last32=Kalyani |first32=Rita R. |last33=Kooperberg |first33=Charles |last34=Kral |first34=Brian G. |last35=Lange |first35=Leslie A. |last36=Lin |first36=Bridget M. |last37=Manichaikul |first37=Ani |last38=Manning |first38=Alisa K. |last39=Martin |first39=Lisa W. |last40=Mathias |first40=Rasika A. |last41=Meigs |first41=James B. |last42=Mitchell |first42=Braxton D. |last43=Montasser |first43=May E. |last44=Morrison |first44=Alanna C. |last45=Naseri |first45=Take |last46=O'Connell |first46=Jeffrey R. |last47=Palmer |first47=Nicholette D. |last48=Peyser |first48=Patricia A. |last49=Psaty |first49=Bruce M. |last50=Raffield |first50=Laura M. |last51=Redline |first51=Susan |last52=Reiner |first52=Alexander P. |last53=Reupena |first53=Muagututi'a Sefuiva |last54=Rice |first54=Kenneth M. |last55=Rich |first55=Stephen S. |last56=Smith |first56=Jennifer A. |last57=Taylor |first57=Kent D. |last58=Taub |first58=Margaret A. |last59=Vasan |first59=Ramachandran S. |last60=Weeks |first60=Daniel E. |last61=Wilson |first61=James G. |last62=Yanek |first62=Lisa R. |last63=Zhao |first63=Wei |last64=Abe |first64=Namiko |last65=Abecasis |first65=Gonçalo |last66=Aguet |first66=Francois |last67=Albert |first67=Christine |last68=Almasy |first68=Laura |last69=Alonso |first69=Alvaro |last70=Ament |first70=Seth |last71=Anderson |first71=Peter |last72=Anugu |first72=Pramod |last73=Applebaum-Bowden |first73=Deborah |last74=Ardlie |first74=Kristin |last75=Arking |first75=Dan |last76=Ashley-Koch |first76=Allison |last77=Aslibekyan |first77=Stella |last78=Assimes |first78=Tim |last79=Avramopoulos |first79=Dimitrios |last80=Ayas |first80=Najib |last81=Balasubramanian |first81=Adithya |last82=Barnard |first82=John |last83=Barnes |first83=Kathleen |last84=Barr |first84=R. Graham |last85=Barron-Casella |first85=Emily |last86=Barwick |first86=Lucas |last87=Beaty |first87=Terri |last88=Beck |first88=Gerald |last89=Becker |first89=Diane |last90=Becker |first90=Lewis |last91=Beer |first91=Rebecca |last92=Beitelshees |first92=Amber |last93=Benjamin |first93=Emelia |last94=Benos |first94=Takis |last95=Bezerra |first95=Marcos |last96=Blue |first96=Nathan |last97=Bowler |first97=Russell |last98=Broeckel |first98=Ulrich |last99=Broome |first99=Jai |last100=Brown |first100=Deborah |last101=Bunting |first101=Karen |last102=Burchard |first102=Esteban |last103=Bustamante |first103=Carlos |last104=Buth |first104=Erin |last105=Cardwell |first105=Jonathan |last106=Carey |first106=Vincent |last107=Carrier |first107=Julie |last108=Carson |first108=April |last109=Carty |first109=Cara |last110=Casaburi |first110=Richard |last111=Casas Romero |first111=Juan P. |last112=Casella |first112=James |last113=Castaldi |first113=Peter |last114=Chaffin |first114=Mark |last115=Chang |first115=Christy |last116=Chang |first116=Yi-Cheng |last117=Chasman |first117=Daniel |last118=Chavan |first118=Sameer |last119=Chen |first119=Bo-Juen |last120=Chen |first120=Wei-Min |last121=Chen |first121=Yii-Der Ida |last122=Cho |first122=Michael |last123=Choi |first123=Seung Hoan |last124=Chuang |first124=Lee-Ming |last125=Chung |first125=Mina |last126=Chung |first126=Ren-Hua |last127=Clish |first127=Clary |last128=Comhair |first128=Suzy |last129=Cornell |first129=Elaine |last130=Crandall |first130=Carolyn |last131=Crapo |first131=James |last132=Curtis |first132=Jeffrey |last133=Custer |first133=Brian |last134=Damcott |first134=Coleen |last135=Darbar |first135=Dawood |last136=David |first136=Sean |last137=Davis |first137=Colleen |last138=Daya |first138=Michelle |last139=de Andrade |first139=Mariza |last140=Fuentes |first140=Lisa de las |last141=DeBaun |first141=Michael |last142=Deka |first142=Ranjan |last143=DeMeo |first143=Dawn |last144=Devine |first144=Scott |last145=Dinh |first145=Huyen |last146=Doddapaneni |first146=Harsha |last147=Duan |first147=Qing |last148=Dugan-Perez |first148=Shannon |last149=Durda |first149=Jon Peter |last150=Dutcher |first150=Susan K. |last151=Eaton |first151=Charles |last152=Ekunwe |first152=Lynette |last153=El Boueiz |first153=Adel |last154=Ellinor |first154=Patrick |last155=Emery |first155=Leslie |last156=Erzurum |first156=Serpil |last157=Farber |first157=Charles |last158=Farek |first158=Jesse |last159=Fingerlin |first159=Tasha |last160=Flickinger |first160=Matthew |last161=Fornage |first161=Myriam |last162=Frazar |first162=Chris |last163=Fu |first163=Mao |last164=Fullerton |first164=Stephanie M. |last165=Fulton |first165=Lucinda |last166=Gabriel |first166=Stacey |last167=Gan |first167=Weiniu |last168=Gao |first168=Shanshan |last169=Gao |first169=Yan |last170=Gass |first170=Margery |last171=Geiger |first171=Heather |last172=Gelb |first172=Bruce |last173=Geraci |first173=Mark |last174=Germer |first174=Soren |last175=Gerszten |first175=Robert |last176=Ghosh |first176=Auyon |last177=Gibbs |first177=Richard |last178=Gignoux |first178=Chris |last179=Gladwin |first179=Mark |last180=Glahn |first180=David |last181=Gogarten |first181=Stephanie |last182=Gong |first182=Da-Wei |last183=Graw |first183=Sharon |last184=Gray |first184=Kathryn J. |last185=Grine |first185=Daniel |last186=Gross |first186=Colin |last187=Gu |first187=C. Charles |last188=Guan |first188=Yue |last189=Gupta |first189=Namrata |last190=Hall |first190=Michael |last191=Han |first191=Yi |last192=Hanly |first192=Patrick |last193=Harris |first193=Daniel |last194=Hawley |first194=Nicola L. |last195=He |first195=Jiang |last196=Heavner |first196=Ben |last197=Heckbert |first197=Susan |last198=Hernandez |first198=Ryan |last199=Herrington |first199=David |last200=Hersh |first200=Craig |last201=Hidalgo |first201=Bertha |last202=Hixson |first202=James |last203=Hobbs |first203=Brian |last204=Hokanson |first204=John |last205=Hong |first205=Elliott |last206=Hoth |first206=Karin |last207=Hsiung |first207=Chao |last208=Hu |first208=Jianhong |last209=Hung |first209=Yi-Jen |last210=Huston |first210=Haley |last211=Hwu |first211=Chii Min |last212=Irvin |first212=Marguerite Ryan |last213=Jackson |first213=Rebecca |last214=Jain |first214=Deepti |last215=Jaquish |first215=Cashell |last216=Johnsen |first216=Jill |last217=Johnson |first217=Andrew |last218=Johnson |first218=Craig |last219=Johnston |first219=Rich |last220=Jones |first220=Kimberly |last221=Kang |first221=Hyun Min |last222=Kaplan |first222=Robert |last223=Kardia |first223=Sharon |last224=Kelly |first224=Shannon |last225=Kenny |first225=Eimear |last226=Kessler |first226=Michael |last227=Khan |first227=Alyna |last228=Khan |first228=Ziad |last229=Kim |first229=Wonji |last230=Kimoff |first230=John |last231=Kinney |first231=Greg |last232=Konkle |first232=Barbara |last233=Kramer |first233=Holly |last234=Lange |first234=Christoph |last235=Lange |first235=Ethan |last236=Laurie |first236=Cathy |last237=Laurie |first237=Cecelia |last238=LeBoff |first238=Meryl |last239=Lee |first239=Jiwon |last240=Lee |first240=Sandra |last241=Lee |first241=Wen-Jane |last242=LeFaive |first242=Jonathon |last243=Levine |first243=David |last244=Lewis |first244=Joshua |last245=Li |first245=Xiaohui |last246=Li |first246=Yun |last247=Lin |first247=Henry |last248=Lin |first248=Honghuang |last249=Liu |first249=Simin |last250=Liu |first250=Yongmei |last251=Liu |first251=Yu |last252=Loos |first252=Ruth J. F. |last253=Lubitz |first253=Steven |last254=Lunetta |first254=Kathryn |last255=Luo |first255=James |last256=Magalang |first256=Ulysses |last257=Mahaney |first257=Michael |last258=Make |first258=Barry |last259=Manson |first259=JoAnn |last260=Marton |first260=Melissa |last261=Mathai |first261=Susan |last262=May |first262=Susanne |last263=McArdle |first263=Patrick |last264=McDonald |first264=Merry-Lynn |last265=McFarland |first265=Sean |last266=McGoldrick |first266=Daniel |last267=McHugh |first267=Caitlin |last268=McNeil |first268=Becky |last269=Mei |first269=Hao |last270=Menon |first270=Vipin |last271=Mestroni |first271=Luisa |last272=Metcalf |first272=Ginger |last273=Meyers |first273=Deborah A. |last274=Mignot |first274=Emmanuel |last275=Mikulla |first275=Julie |last276=Min |first276=Nancy |last277=Minear |first277=Mollie |last278=Minster |first278=Ryan L. |last279=Moll |first279=Matt |last280=Momin |first280=Zeineen |last281=Montgomery |first281=Courtney |last282=Muzny |first282=Donna |last283=Mychaleckyj |first283=Josyf C. |last284=Nadkarni |first284=Girish |last285=Naik |first285=Rakhi |last286=Nekhai |first286=Sergei |last287=Nelson |first287=Sarah C. |last288=Neltner |first288=Bonnie |last289=Nessner |first289=Caitlin |last290=Nickerson |first290=Deborah |last291=Nkechinyere |first291=Osuji |last292=North |first292=Kari |last293=O'Connor |first293=Tim |last294=Ochs-Balcom |first294=Heather |last295=Okwuonu |first295=Geoffrey |last296=Pack |first296=Allan |last297=Paik |first297=David T. |last298=Pankow |first298=James |last299=Papanicolaou |first299=George |last300=Parker |first300=Cora |last301=Peralta |first301=Juan Manuel |last302=Perez |first302=Marco |last303=Perry |first303=James |last304=Peters |first304=Ulrike |last305=Phillips |first305=Lawrence S. |last306=Pleiness |first306=Jacob |last307=Pollin |first307=Toni |last308=Post |first308=Wendy |last309=Becker |first309=Julia Powers |last310=Boorgula |first310=Meher Preethi |last311=Preuss |first311=Michael |last312=Qasba |first312=Pankaj |last313=Qiao |first313=Dandi |last314=Qin |first314=Zhaohui |last315=Rafaels |first315=Nicholas |last316=Rajendran |first316=Mahitha |last317=Rao |first317=D. C. |last318=Rasmussen-Torvik |first318=Laura |last319=Ratan |first319=Aakrosh |last320=Reed |first320=Robert |last321=Reeves |first321=Catherine |last322=Regan |first322=Elizabeth |last323=Robillard |first323=Rebecca |last324=Robine |first324=Nicolas |last325=Roden |first325=Dan |last326=Roselli |first326=Carolina |last327=Ruczinski |first327=Ingo |last328=Runnels |first328=Alexi |last329=Russell |first329=Pamela |last330=Ruuska |first330=Sarah |last331=Ryan |first331=Kathleen |last332=Sabino |first332=Ester Cerdeira |last333=Saleheen |first333=Danish |last334=Salimi |first334=Shabnam |last335=Salvi |first335=Sejal |last336=Salzberg |first336=Steven |last337=Sandow |first337=Kevin |last338=Sankaran |first338=Vijay G. |last339=Santibanez |first339=Jireh |last340=Schwander |first340=Karen |last341=Schwartz |first341=David |last342=Sciurba |first342=Frank |last343=Seidman |first343=Christine |last344=Seidman |first344=Jonathan |last345=Sériès |first345=Frédéric |last346=Sheehan |first346=Vivien |last347=Sherman |first347=Stephanie L. |last348=Shetty |first348=Amol |last349=Shetty |first349=Aniket |last350=Sheu |first350=Wayne Hui-Heng |last351=Shoemaker |first351=M. Benjamin |last352=Silver |first352=Brian |last353=Silverman |first353=Edwin |last354=Skomro |first354=Robert |last355=Smith |first355=Albert Vernon |last356=Smith |first356=Josh |last357=Smith |first357=Nicholas |last358=Smith |first358=Tanja |last359=Smoller |first359=Sylvia |last360=Snively |first360=Beverly |last361=Snyder |first361=Michael |last362=Sofer |first362=Tamar |last363=Sotoodehnia |first363=Nona |last364=Stilp |first364=Adrienne M. |last365=Storm |first365=Garrett |last366=Streeten |first366=Elizabeth |last367=Su |first367=Jessica Lasky |last368=Sung |first368=Yun Ju |last369=Sylvia |first369=Jody |last370=Szpiro |first370=Adam |last371=Taliun |first371=Daniel |last372=Tang |first372=Hua |last373=Taub |first373=Margaret |last374=Taylor |first374=Matthew |last375=Taylor |first375=Simeon |last376=Telen |first376=Marilyn |last377=Thornton |first377=Timothy A. |last378=Threlkeld |first378=Machiko |last379=Tinker |first379=Lesley |last380=Tirschwell |first380=David |last381=Tishkoff |first381=Sarah |last382=Tiwari |first382=Hemant |last383=Tong |first383=Catherine |last384=Tracy |first384=Russell |last385=Tsai |first385=Michael |last386=Vaidya |first386=Dhananjay |last387=Van Den Berg |first387=David |last388=VandeHaar |first388=Peter |last389=Vrieze |first389=Scott |last390=Walker |first390=Tarik |last391=Wallace |first391=Robert |last392=Walts |first392=Avram |last393=Wang |first393=Fei Fei |last394=Wang |first394=Heming |last395=Wang |first395=Jiongming |last396=Watson |first396=Karol |last397=Watt |first397=Jennifer |last398=Weinstock |first398=Joshua |last399=Weir |first399=Bruce |last400=Weiss |first400=Scott T. |last401=Weng |first401=Lu-Chen |last402=Wessel |first402=Jennifer |last403=Williams |first403=Kayleen |last404=Williams |first404=L. Keoki |last405=Wilson |first405=Carla |last406=Winterkorn |first406=Lara |last407=Wong |first407=Quenna |last408=Wu |first408=Joseph |last409=Xu |first409=Huichun |last410=Yang |first410=Ivana |last411=Yu |first411=Ketian |last412=Zekavat |first412=Seyedeh Maryam |last413=Zhang |first413=Yingze |last414=Zhao |first414=Snow Xueyan |last415=Zhu |first415=Xiaofeng |last416=Ziv |first416=Elad |last417=Zody |first417=Michael |last418=Zoellner |first418=Sebastian |last419=Atkinson |first419=Elizabeth |last420=Ballantyne |first420=Christie |last421=Bao |first421=Wei |last422=Bhattacharya |first422=Romit |last423=Bielak |first423=Larry |last424=Bis |first424=Joshua |last425=Bodea |first425=Corneliu |last426=Brody |first426=Jennifer |last427=Cade |first427=Brian |last428=Calvo |first428=Sarah |last429=Carlson |first429=Jenna |last430=Chang |first430=I-Shou |last431=Cho |first431=So Mi |last432=de Vries |first432=Paul |last433=Diallo |first433=Ana F. |last434=Do |first434=Ron |last435=Dron |first435=Jacqueline |last436=Elliott |first436=Amanda |last437=Finucane |first437=Hilary |last438=Floyd |first438=Caitlin |last439=Ganna |first439=Andrea |last440=Gong |first440=Dawei |last441=Graham |first441=Sarah |last442=Haas |first442=Mary |last443=Haring |first443=Bernhard |last444=Heemann |first444=Scott |last445=Himes |first445=Blanca |last446=Jarvik |first446=Gail |last447=Jiang |first447=Jicai |last448=Joehanes |first448=Roby |last449=Joseph |first449=Paule Valery |last450=Jun |first450=Goo |last451=Kalyani |first451=Rita |last452=Kanai |first452=Masahiro |last453=Kathiresan |first453=Sekar |last454=Khera |first454=Amit |last455=Khetarpal |first455=Sumeet |last456=Klarin |first456=Derek |last457=Koyama |first457=Satoshi |last458=Kral |first458=Brian |last459=Lange |first459=Leslie |last460=Lemaitre |first460=Rozenn |last461=Li |first461=Changwei |last462=Lu |first462=Yingchang |last463=Martin |first463=Lisa |last464=Mathias |first464=Rasika |last465=Mathur |first465=Ravi |last466=McGarvey |first466=Stephen |last467=McLenithan |first467=John |last468=Miller |first468=Amy |last469=Mootha |first469=Vamsi |last470=Moran |first470=Andrew |last471=Nakao |first471=Tetsushi |last472=O'Connell |first472=Jeff |last473=O'Donnell |first473=Christopher |last474=Palmer |first474=Nicholette |last475=Paruchuri |first475=Kaavya |last476=Patel |first476=Aniruddh |last477=Peloso |first477=Gina |last478=Pettinger |first478=Mary |last479=Peyser |first479=Patricia |last480=Pirruccello |first480=James |last481=Psaty |first481=Bruce |last482=Reiner |first482=Alex |last483=Rich |first483=Stephen |last484=Rosenthal |first484=Samantha |last485=Rotter |first485=Jerome |last486=Smith |first486=Jennifer |last487=Sunyaev |first487=Shamil R. |last488=Surakka |first488=Ida |last489=Sztalryd |first489=Carole |last490=Trinder |first490=Mark |last491=Uddin |first491=Md Mesbah |last492=Urbut |first492=Sarah |last493=Van Buren |first493=Eric |last494=Verbanck |first494=Marie |last495=Von Holle |first495=Ann |last496=Wang |first496=Yuxuan |last497=Wiggins |first497=Kerri |last498=Wilkins |first498=John |last499=Willer |first499=Cristen |last500=Wilson |first500=James |last501=Wolford |first501=Brooke |last502=Yanek |first502=Lisa |last503=Yu |first503=Zhi |last504=Zaghloul |first504=Norann |last505=Zhang |first505=Jingwen |last506=Zhou |first506=Ying |last507=Rotter |first507=Jerome I. |last508=Willer |first508=Cristen J. |last509=Natarajan |first509=Pradeep |last510=Peloso |first510=Gina M. |last511=Lin |first511=Xihong|title=A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies |journal=Nature Methods |date=December 2022 |volume=19 |issue=12 |pages=1599–1611 |doi=10.1038/s41592-022-01640-x|pmid=36303018 |pmc=10008172 |s2cid=243873361 }}</ref><ref>{{cite journal |title=STAARpipeline: an all-in-one rare-variant tool for biobank-scale whole-genome sequencing data |journal=Nature Methods |date=December 2022 |volume=19 |issue=12 |pages=1532–1533 |doi=10.1038/s41592-022-01641-w|pmid=36316564 |s2cid=253246835 }}</ref> Meta-analysis of whole genome sequencing studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes.<ref>{{cite journal |last1=Li |first1=Xihao |last2=Quick |first2=Corbin |last3=Zhou |first3=Hufeng |last4=Gaynor |first4=Sheila M. |last5=Liu |first5=Yaowu |last6=Chen |first6=Han |last7=Selvaraj |first7=Margaret Sunitha |last8=Sun |first8=Ryan |last9=Dey |first9=Rounak |last10=Arnett |first10=Donna K. |last11=Bielak |first11=Lawrence F. |last12=Bis |first12=Joshua C. |last13=Blangero |first13=John |last14=Boerwinkle |first14=Eric |last15=Bowden |first15=Donald W. |last16=Brody |first16=Jennifer A. |last17=Cade |first17=Brian E. |last18=Correa |first18=Adolfo |last19=Cupples |first19=L. Adrienne |last20=Curran |first20=Joanne E. |last21=de Vries |first21=Paul S. |last22=Duggirala |first22=Ravindranath |last23=Freedman |first23=Barry I. |last24=Göring |first24=Harald H. H. |last25=Guo |first25=Xiuqing |last26=Haessler |first26=Jeffrey |last27=Kalyani |first27=Rita R. |last28=Kooperberg |first28=Charles |last29=Kral |first29=Brian G. |last30=Lange |first30=Leslie A. |last31=Manichaikul |first31=Ani |last32=Martin |first32=Lisa W. |last33=McGarvey |first33=Stephen T. |last34=Mitchell |first34=Braxton D. |last35=Montasser |first35=May E. |last36=Morrison |first36=Alanna C. |last37=Naseri |first37=Take |last38=O'Connell |first38=Jeffrey R. |last39=Palmer |first39=Nicholette D. |last40=Peyser |first40=Patricia A. |last41=Psaty |first41=Bruce M. |last42=Raffield |first42=Laura M. |last43=Redline |first43=Susan |last44=Reiner |first44=Alexander P. |last45=Reupena |first45=Muagututi'a Sefuiva |last46=Rice |first46=Kenneth M. |last47=Rich |first47=Stephen S. |last48=Sitlani |first48=Colleen M. |last49=Smith |first49=Jennifer A. |last50=Taylor |first50=Kent D. |last51=Vasan |first51=Ramachandran S. |last52=Willer |first52=Cristen J. |last53=Wilson |first53=James G. |last54=Yanek |first54=Lisa R. |last55=Zhao |first55=Wei |last56=NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium|last57=TOPMed Lipids Working Group
|last58=Rotter |first58=Jerome I. |last59=Natarajan |first59=Pradeep |last60=Peloso |first60=Gina M. |last61=Li |first61=Zilin |last62=Lin |first62=Xihong |title=Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies |journal=Nature Genetics |date=January 2023 |volume=55 |issue=1 |pages=154–164 |doi=10.1038/s41588-022-01225-6|pmid=36564505 |pmc=10084891 |s2cid=255084231 }}</ref>

===Analysis of mutations in cancer===
{{main|Oncogenomics}}

In [[cancer]], the genomes of affected cells are rearranged in complex or unpredictable ways. In addition to [[single-nucleotide polymorphism]] arrays identifying [[point mutation]]s that cause cancer, [[oligonucleotide]] microarrays can be used to identify chromosomal gains and losses (called [[comparative genomic hybridization]]). These detection methods generate [[terabyte]]s of data per experiment. The data is often found to contain considerable variability, or [[noise]], and thus [[Hidden Markov model]] and change-point analysis methods are being developed to infer real [[copy number]] changes.{{Citation needed|date=June 2023}}

Two important principles can be used to identify cancer by mutations in the [[exome]]. First, cancer is a disease of accumulated somatic mutations in genes. Second, cancer contains driver mutations which need to be distinguished from passengers.<ref>{{cite journal | vauthors = Vazquez M, de la Torre V, Valencia A | title = Chapter 14: Cancer genome analysis | journal = PLOS Computational Biology | volume = 8 | issue = 12 | pages = e1002824 | date = 2012-12-27 | pmid = 23300415 | pmc = 3531315 | doi = 10.1371/journal.pcbi.1002824 | bibcode = 2012PLSCB...8E2824V | doi-access = free }}</ref>

Further improvements in bioinformatics could allow for classifying types of cancer by analysis of cancer driven mutations in the genome. Furthermore, tracking of patients while the disease progresses may be possible in the future with the sequence of cancer samples. Another type of data that requires novel informatics development is the analysis of [[lesion]]s found to be recurrent among many tumors.<ref>{{cite book | vauthors = Hye-Jung EC, Jaswinder K, Martin K, Samuel AA, Marco AM | veditors = Dellaire G, Berman JN, Arceci RJ | title= Cancer Genomics |date=2014 |publisher=Academic Press |location=Boston (US) |isbn=978-0-12-396967-5 |pages=13–30 |chapter=Second-Generation Sequencing for Cancer Genome Analysis |doi=10.1016/B978-0-12-396967-5.00002-5}}</ref>