Editing Human genome (section)

== Genomic variation in humans ==
{{Main|Human genetic variation}}

=== Human reference genome ===

With the exception of identical twins, all humans show significant variation in genomic DNA sequences. The human [[reference genome]] (HRG) is used as a standard sequence reference.

There are several important points concerning the human reference genome:
* The HRG is a haploid sequence. Each chromosome is represented once.
* The HRG is a composite sequence, and does not correspond to any actual human individual.
* The HRG is periodically updated to correct errors, ambiguities, and unknown "gaps".
* The HRG in no way represents an "ideal" or "perfect" human individual. It is simply a standardized representation or model that is used for comparative purposes.

The [[Genome Reference Consortium]] is responsible for updating the HRG. Version 38 was released in December 2013.<ref name="NCBI GRCh38">{{Cite web|url=https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.26/|title=GRCh38 – hg38 – Genome – Assembly |author=NCBI|website=ncbi.nlm.nih.gov|access-date=2019-03-15|author-link=National Center for Biotechnology Information}}</ref>

=== Measuring human genetic variation ===

Most studies of human genetic variation have focused on [[single-nucleotide polymorphism]]s (SNPs), which are substitutions in individual bases along a chromosome. Most analyses estimate that SNPs occur 1 in 1000 base pairs, on average, in the [[euchromatin|euchromatic]] human genome, although they do not occur at a uniform density. Thus follows the popular statement that "we are all, regardless of [[Race (classification of human beings)|race]], genetically 99.9% the same",<ref>{{Cite web |url=http://clinton4.nara.gov/WH/SOTU00/sotu-text.html |title=from Bill Clinton's 2000 State of the Union address |access-date=14 June 2007 |archive-url=https://web.archive.org/web/20170221025546/https://clinton4.nara.gov/WH/SOTU00/sotu-text.html |archive-date=21 February 2017 |url-status=dead }}</ref> although this would be somewhat qualified by most geneticists. For example, a much larger fraction of the genome is now thought to be involved in [[copy number variation]].<ref>{{cite journal | vauthors = Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME | title = Global variation in copy number in the human genome | journal = Nature | volume = 444 | issue = 7118 | pages = 444–454 | date = November 2006 | pmid = 17122850 | pmc = 2669898 | doi = 10.1038/nature05329 | bibcode = 2006Natur.444..444R }}</ref> A large-scale collaborative effort to catalog SNP variations in the human genome is being undertaken by the [[International HapMap Project]].{{citation needed|date=March 2023}}

The genomic loci and length of certain types of small [[Repeated sequence (DNA)|repetitive sequences]] are highly variable from person to person, which is the basis of [[DNA fingerprinting]] and [[DNA paternity testing]] technologies. The [[heterochromatin|heterochromatic]] portions of the human genome, which total several hundred million base pairs, are also thought to be quite variable within the human population (they are so repetitive and so long that they cannot be accurately sequenced with current technology). These regions contain few genes, and it is unclear whether any significant [[phenotype|phenotypic]] effect results from typical variation in repeats or heterochromatin.

Most gross genomic mutations in [[gamete]] germ cells probably result in inviable embryos; however, a number of human diseases are related to large-scale genomic abnormalities. [[Down syndrome]], [[Turner Syndrome]], and a number of other diseases result from [[nondisjunction]] of entire chromosomes. [[Cancer]] cells frequently have [[aneuploidy]] of chromosomes and chromosome arms, although a [[Causality|cause and effect]] relationship between aneuploidy and cancer has not been established.

==== Mapping human genomic variation ====

Whereas a genome sequence lists the order of every DNA base in a genome, a genome map identifies the landmarks. A genome map is less detailed than a genome sequence and aids in navigating around the genome.<ref>{{Cite web|url=http://www.genomenewsnetwork.org/resources/whats_a_genome/Chp3_1.shtml |title=What's a Genome? |publisher=Genomenewsnetwork.org |date=15 January 2003 |access-date=31 May 2009}}</ref><ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/About/primer/mapping.html | title = Fact Sheet: Genome Mapping: A Guide to the Genetic Highway We Call the Human Genome | work = National Center for Biotechnology Information | publisher = U.S. National Library of Medicine, National Institutes of Health | date = 29 March 2004 | access-date = 31 May 2009 | url-status = dead | archive-url = https://web.archive.org/web/20100719235548/http://www.ncbi.nlm.nih.gov/About/primer/mapping.html | archive-date = 19 July 2010 | df = dmy-all }}</ref>

An example of a variation map is the HapMap being developed by the [[International HapMap Project]]. The HapMap is a [[haplotype]] map of the human genome, "which will describe the common patterns of human DNA sequence variation."<ref>{{Cite web |url=http://www.hapmap.org/abouthapmap.html |title= About the Project | work = International HapMap Project |access-date=31 May 2009 |archive-date=15 May 2008 |archive-url=https://web.archive.org/web/20080515164605/http://www.hapmap.org/abouthapmap.html |url-status=dead }}</ref> It catalogs the patterns of small-scale variations in the genome that involve single DNA letters, or bases.

Researchers published the first sequence-based map of large-scale structural variation across the human genome in the journal ''[[Nature (journal)|Nature]]'' in May 2008.<ref>{{Cite web|url=http://www.genome.gov/27026113 |title=2008 Release: Researchers Produce First Sequence Map of Large-Scale Structural Variation in the Human Genome |publisher=genome.gov |access-date=31 May 2009}}</ref><ref name="pmid18451855">{{cite journal | vauthors = Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T, Hansen N, Teague B, Alkan C, Antonacci F, Haugen E, Zerr T, Yamada NA, Tsang P, Newman TL, Tüzün E, Cheng Z, Ebling HM, Tusneem N, David R, Gillett W, Phelps KA, Weaver M, Saranga D, Brand A, Tao W, Gustafson E, McKernan K, Chen L, Malig M, Smith JD, Korn JM, McCarroll SA, Altshuler DA, Peiffer DA, Dorschner M, Stamatoyannopoulos J, Schwartz D, Nickerson DA, Mullikin JC, Wilson RK, Bruhn L, Olson MV, Kaul R, Smith DR, Eichler EE | title = Mapping and sequencing of structural variation from eight human genomes | journal = Nature | volume = 453 | issue = 7191 | pages = 56–64 | date = May 2008 | pmid = 18451855 | pmc = 2424287 | doi = 10.1038/nature06862 | bibcode = 2008Natur.453...56K }}</ref> Large-scale structural variations are differences in the genome among people that range from a few thousand to a few million DNA bases; some are gains or losses of stretches of genome sequence and others appear as re-arrangements of stretches of sequence. These variations include [[copy number variation|differences in the number of copies]] individuals have of a particular gene, deletions, translocations and inversions.

=== Structural variation ===
Structural variation refers to genetic variants that affect larger segments of the human genome, as opposed to point [[mutation]]s. Often, structural variants (SVs) are defined as variants of 50 base pairs (bp) or greater, such as deletions, duplications, insertions, inversions and other rearrangements. About 90% of structural variants are noncoding deletions but most individuals have more than a thousand such deletions; the size of deletions ranges from dozens of base pairs to tens of thousands of bp.<ref name=":2">{{cite journal | vauthors = Abel HJ, Larson DE, Regier AA, Chiang C, Das I, Kanchi KL, Layer RM, Neale BM, Salerno WJ, Reeves C, Buyske S, Matise TC, Muzny DM, Zody MC, Lander ES, Dutcher SK, Stitziel NO, Hall IM | title = Mapping and characterization of structural variation in 17,795 human genomes | journal = Nature | volume = 583 | issue = 7814 | pages = 83–89 | date = July 2020 | pmid = 32460305 | pmc = 7547914 | doi = 10.1038/s41586-020-2371-0 | bibcode = 2020Natur.583...83A }}</ref> On average, individuals carry ~3 rare structural variants that alter coding regions, e.g. delete [[exon]]s. About 2% of individuals carry ultra-rare megabase-scale structural variants, especially rearrangements. That is, millions of base pairs may be inverted within a chromosome; ultra-rare means that they are only found in individuals or their family members and thus have arisen very recently.<ref name=":2" />

=== SNP frequency across the human genome ===

Single-nucleotide polymorphisms (SNPs) do not occur homogeneously across the human genome. In fact, there is enormous diversity in [[Single-nucleotide polymorphism|SNP]] frequency between genes, reflecting different selective pressures on each gene as well as different mutation and recombination rates across the genome. However, studies on SNPs are biased towards coding regions, the data generated from them are unlikely to reflect the overall distribution of SNPs throughout the genome. Therefore, the [[SNP Consortium]] protocol was designed to identify SNPs with no bias towards coding regions and the Consortium's 100,000 SNPs generally reflect sequence diversity across the human chromosomes. The [[SNP Consortium]] aims to expand the number of SNPs identified across the genome to 300 000 by the end of the first quarter of 2001.<ref>{{cite journal |pmid=11005795 | volume=9 | issue=16 | title=Single nucleotide polymorphisms as tools in human genetics | year=2000 | journal=Human Molecular Genetics | pages=2403–2408 | doi=10.1093/hmg/9.16.2403 | vauthors=Gray IC, Campbell DA, Spurr NK| doi-access=free }}</ref> [[File:TSC SNP Distribution.jpg|thumb|TSC SNP distribution along the long arm of chromosome 22 (from https://web.archive.org/web/20130903043223/http://snp.cshl.org/ ). Each column represents a 1 Mb interval; the approximate cytogenetic position is given on the x-axis. Clear peaks and troughs of SNP density can be seen, possibly reflecting different rates of mutation, recombination and selection.]]Changes in '''non-coding sequence''' and synonymous changes in '''coding sequence''' are generally more common than non-synonymous changes, reflecting greater selective pressure reducing diversity at positions dictating amino acid identity. Transitional changes are more common than transversions, with CpG dinucleotides showing the highest mutation rate, presumably due to deamination.{{citation needed|date=March 2023}}

=== Personal genomes ===
{{See also|Personal genomics}}

A personal genome sequence is a (nearly) complete [[DNA sequencing|sequence]] of the chemical base pairs that make up the [[DNA]] of a single person. Because medical treatments have different effects on different people due to genetic variations such as [[single-nucleotide polymorphisms]] (SNPs), the analysis of personal genomes may lead to personalized medical treatment based on individual genotypes.<ref>{{cite journal | vauthors = Lai E | title = Application of SNP technologies in medicine: lessons learned and future challenges | journal = Genome Research | volume = 11 | issue = 6 | pages = 927–929 | date = June 2001 | pmid = 11381021 | doi = 10.1101/gr.192301 | doi-access = free }}</ref>

The first personal genome sequence to be determined was that of [[Craig Venter]] in 2007. Personal genomes had not been sequenced in the public Human Genome Project to protect the identity of volunteers who provided DNA samples. That sequence was derived from the DNA of several volunteers from a diverse population.<ref>{{Cite web|url=http://www.genome.gov/11006943 |title=Human Genome Project Completion: Frequently Asked Questions |publisher=genome.gov |access-date=31 May 2009}}</ref> However, early in the Venter-led [[Celera Genomics]] genome sequencing effort the decision was made to switch from sequencing a composite sample to using DNA from a single individual, later revealed to have been Venter himself. Thus the Celera human genome sequence released in 2000 was largely that of one man. Subsequent replacement of the early composite-derived data and determination of the diploid sequence, representing both sets of [[chromosomes]], rather than a haploid sequence originally reported, allowed the release of the first personal genome.<ref name="dna switch">{{cite news |vauthors=Singer E |url=http://www.technologyreview.com/biomedicine/19328/?a=f |title=Craig Venter's Genome |newspaper=[[MIT Technology Review]] |date=4 September 2007 |access-date=25 May 2010 |archive-date=7 June 2011 |archive-url=https://web.archive.org/web/20110607104347/http://www.technologyreview.com/biomedicine/19328/?a=f |url-status=dead }}</ref> In April 2008, that of [[James Watson]] was also completed. In 2009, Stephen Quake published his own genome sequence derived from a sequencer of his own design, the Heliscope.<ref>{{cite journal | vauthors = Pushkarev D, Neff NF, Quake SR | title = Single-molecule sequencing of an individual human genome | journal = Nature Biotechnology | volume = 27 | issue = 9 | pages = 847–850 | date = September 2009 | pmid = 19668243 | pmc = 4117198 | doi = 10.1038/nbt.1561 }}</ref> A Stanford team led by [[Euan Ashley]] published a framework for the medical interpretation of human genomes implemented on Quake's genome and made whole genome-informed medical decisions for the first time.<ref>{{cite journal | vauthors = Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, Pushkarev D, Neff NF, Hudgins L, Gong L, Hodges LM, Berlin DS, Thorn CF, Sangkuhl K, Hebert JM, Woon M, Sagreiya H, Whaley R, Knowles JW, Chou MF, Thakuria JV, Rosenbaum AM, Zaranek AW, Church GM, Greely HT, Quake SR, Altman RB | title = Clinical assessment incorporating a personal genome | journal = Lancet | volume = 375 | issue = 9725 | pages = 1525–1535 | date = May 2010 | pmc = 2937184 | doi = 10.1016/S0140-6736(10)60452-7 | pmid = 20435227 }}</ref> That team further extended the approach to the West family, the first family sequenced as part of Illumina's Personal Genome Sequencing program.<ref>{{cite journal | vauthors = Dewey FE, Chen R, Cordero SP, Ormond KE, Caleshu C, Karczewski KJ, Whirl-Carrillo M, Wheeler MT, Dudley JT, Byrnes JK, Cornejo OE, Knowles JW, Woon M, Sangkuhl K, Gong L, Thorn CF, Hebert JM, Capriotti E, David SP, Pavlovic A, West A, Thakuria JV, Ball MP, Zaranek AW, Rehm HL, Church GM, West JS, Bustamante CD, Snyder M, Altman RB, Klein TE, Butte AJ, Ashley EA | title = Phased whole-genome genetic risk in a family quartet using a major allele reference sequence | journal = PLOS Genetics | volume = 7 | issue = 9 | pages = e1002280 | date = September 2011 | pmid = 21935354 | doi = 10.1371/journal.pgen.1002280 | pmc = 3174201 | doi-access = free }}</ref> Since then hundreds of personal genome sequences have been released,<ref>{{cite press release | title = Complete Genomics Adds 29 High-Coverage, Complete Human Genome Sequencing Datasets to Its Public Genomic Repository | url = http://globenewswire.com/news-release/2011/04/06/443810/218032/en/Complete-Genomics-Adds-29-High-Coverage-Complete-Human-Genome-Sequencing-Datasets-to-Its-Public-Genomic-Repository.html?print=1  }}</ref> including those of [[Desmond Tutu]],<ref>{{cite web | url = https://www.theguardian.com/science/2010/feb/17/desmond-tutu-genome-genetic-diversity | title = Desmond Tutu's genome sequenced as part of genetic diversity study | vauthors = Sample I | work = The Guardian | date = 17 February 2010 }}</ref><ref name="pmid20164927">{{cite journal | vauthors = Schuster SC, Miller W, Ratan A, Tomsho LP, Giardine B, Kasson LR, Harris RS, Petersen DC, Zhao F, Qi J, Alkan C, Kidd JM, Sun Y, Drautz DI, Bouffard P, Muzny DM, Reid JG, Nazareth LV, Wang Q, Burhans R, Riemer C, Wittekindt NE, Moorjani P, Tindall EA, Danko CG, Teo WS, Buboltz AM, Zhang Z, Ma Q, Oosthuysen A, Steenkamp AW, Oostuisen H, Venter P, Gajewski J, Zhang Y, Pugh BF, Makova KD, Nekrutenko A, Mardis ER, Patterson N, Pringle TH, Chiaromonte F, Mullikin JC, Eichler EE, Hardison RC, Gibbs RA, Harkins TT, Hayes VM | title = Complete Khoisan and Bantu genomes from southern Africa | journal = Nature | volume = 463 | issue = 7283 | pages = 943–947 | date = February 2010 | pmid = 20164927 | pmc = 3890430 | doi = 10.1038/nature08795 | bibcode = 2010Natur.463..943S }}</ref> and of a [[Paleo-Eskimo]].<ref>{{cite journal | vauthors = Rasmussen M, Li Y, Lindgreen S, Pedersen JS, Albrechtsen A, Moltke I, Metspalu M, Metspalu E, Kivisild T, Gupta R, Bertalan M, Nielsen K, Gilbert MT, Wang Y, Raghavan M, Campos PF, Kamp HM, Wilson AS, Gledhill A, Tridico S, Bunce M, Lorenzen ED, Binladen J, Guo X, Zhao J, Zhang X, Zhang H, Li Z, Chen M, Orlando L, Kristiansen K, Bak M, Tommerup N, Bendixen C, Pierre TL, Grønnow B, Meldgaard M, Andreasen C, Fedorova SA, Osipova LP, Higham TF, Ramsey CB, Hansen TV, Nielsen FC, Crawford MH, Brunak S, Sicheritz-Pontén T, Villems R, Nielsen R, Krogh A, Wang J, Willerslev E | title = Ancient human genome sequence of an extinct Palaeo-Eskimo | journal = Nature | volume = 463 | issue = 7282 | pages = 757–762 | date = February 2010 | pmid = 20148029 | pmc = 3951495 | doi = 10.1038/nature08835 | bibcode = 2010Natur.463..757R }}</ref> In 2012, the whole genome sequences of two family trios among 1092 genomes was made public.<ref name="nature.com"/> In November 2013, a Spanish family made four personal exome datasets (about 1% of the genome) publicly available under a [[CC0#Zero / Public domain|Creative Commons public domain license]].<ref>{{cite bioRxiv | vauthors = Corpas M, Cariaso M, Coletta A, Weiss D, Harrison AP, Moran F, Yang H | author-link1 = Manuel Corpas (Scientist) | title = A Complete Public Domain Family Genomics Dataset  | date = 12 November 2013 | biorxiv = 10.1101/000216 }}</ref><ref>{{cite journal | vauthors = Corpas M | title = Crowdsourcing the corpasome | journal = Source Code for Biology and Medicine | volume = 8 | issue = 1 | pages = 13 | date = June 2013 | pmid = 23799911 | pmc = 3706263 | doi = 10.1186/1751-0473-8-13 | author-link1 = Manuel Corpas (Scientist) | doi-access = free }}</ref> The [[Personal Genome Project]] (started in 2005) is among the few to make both genome sequences and corresponding medical phenotypes publicly available.<ref>{{cite journal | vauthors = Mao Q, Ciotlos S, Zhang RY, Ball MP, Chin R, Carnevali P, Barua N, Nguyen S, Agarwal MR, Clegg T, Connelly A, Vandewege W, Zaranek AW, Estep PW, Church GM, Drmanac R, Peters BA | title = The whole genome sequences and experimentally phased haplotypes of over 100 personal genomes | journal = GigaScience | volume = 5 | issue = 1 | pages = 42 | date = October 2016 | pmid = 27724973 | pmc = 5057367 | doi = 10.1186/s13742-016-0148-z | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cai B, Li B, Kiga N, Thusberg J, Bergquist T, Chen YC, Niknafs N, Carter H, Tokheim C, Beleva-Guthrie V, Douville C, Bhattacharya R, Yeo HT, Fan J, Sengupta S, Kim D, Cline M, Turner T, Diekhans M, Zaucha J, Pal LR, Cao C, Yu CH, Yin Y, Carraro M, Giollo M, Ferrari C, Leonardi E, Tosatto SC, Bobe J, Ball M, Hoskins RA, Repo S, Church G, Brenner SE, Moult J, Gough J, Stanke M, Karchin R, Mooney SD | title = Matching phenotypes to whole genomes: Lessons learned from four iterations of the personal genome project community challenges | journal = Human Mutation | volume = 38 | issue = 9 | pages = 1266–1276 | date = September 2017 | pmid = 28544481 | pmc = 5645203 | doi = 10.1002/humu.23265 }}</ref>

The sequencing of individual genomes further unveiled levels of genetic complexity that had not been appreciated before. Personal genomics helped reveal the significant level of diversity in the human genome attributed not only to SNPs but structural variations as well. However, the application of such knowledge to the treatment of disease and in the medical field is only in its very beginnings.<ref>{{cite journal | vauthors = Gonzaga-Jauregui C, Lupski JR, Gibbs RA | title = Human genome sequencing in health and disease | journal = Annual Review of Medicine | volume = 63 | pages = 35–61 | year = 2012 | pmid = 22248320 | doi = 10.1146/annurev-med-051010-162644 | pmc = 3656720 }}</ref> [[Exome sequencing]] has become increasingly popular as a tool to aid in diagnosis of genetic disease because the exome contributes only 1% of the genomic sequence but accounts for roughly 85% of mutations that contribute significantly to disease.<ref>{{cite journal | vauthors = Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP | title = Genetic diagnosis by whole exome capture and massively parallel DNA sequencing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 45 | pages = 19096–19101 | date = Nov 2009 | pmid = 19861545 | pmc = 2768590 | doi = 10.1073/pnas.0910672106 | bibcode = 2009PNAS..10619096C | doi-access = free }}</ref>

=== Human knockouts ===

In humans, [[gene knockouts]] naturally occur as [[heterozygous]] or [[homozygous]] [[loss-of-function]] gene knockouts. These knockouts are often difficult to distinguish, especially within [[heterogeneous]] genetic backgrounds. They are also difficult to find as they occur in low frequencies.
[[File:Gene Knockouts in Outbred vs. Parentally-related populations.jpg|thumb|Populations with a high level of parental-relatedness result in a larger number of homozygous gene knockouts as compared to outbred populations.<ref name="Narasimhan VM 2016">{{cite journal | vauthors = Narasimhan VM, Xue Y, Tyler-Smith C | title = Human Knockout Carriers: Dead, Diseased, Healthy, or Improved? | journal = Trends in Molecular Medicine | volume = 22 | issue = 4 | pages = 341–351 | date = April 2016 | pmid = 26988438 | pmc = 4826344 | doi = 10.1016/j.molmed.2016.02.006 }}</ref>]]

Populations with high rates of [[consanguinity]], such as countries with high rates of first-cousin marriages, display the highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize the gene that has been knocked out.

[[File:Consanguineous Mating resulting in Knockout.jpg|thumb|A pedigree displaying a first-cousin mating (carriers both carrying heterozygous knockouts mating as marked by double line) leading to offspring possessing a homozygous gene knockout]]

Knockouts in specific genes can cause genetic diseases, potentially have beneficial effects, or even result in no phenotypic effect at all. However, determining a knockout's phenotypic effect and in humans can be challenging. Challenges to characterizing and clinically interpreting knockouts include difficulty calling of DNA variants, determining disruption of protein function (annotation), and considering the amount of influence [[mosaicism]] has on the phenotype.<ref name="Narasimhan VM 2016"/>

One major study that investigated human knockouts is the Pakistan Risk of Myocardial Infarction study. It was found that individuals possessing a heterozygous loss-of-function gene knockout for the [[APOC3]] gene had lower triglycerides in the blood after consuming a high fat meal as compared to individuals without the mutation. However, individuals possessing homozygous loss-of-function gene knockouts of the APOC3 gene displayed the lowest level of triglycerides in the blood after the fat load test, as they produce no functional APOC3 protein.<ref>{{cite journal | vauthors = Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SN, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S  | title = Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity | journal = Nature | volume = 544 | issue = 7649 | pages = 235–239 | date = April 2017 | pmid = 28406212 | pmc = 5600291 | doi = 10.1038/nature22034 | bibcode = 2017Natur.544..235S }}</ref>

===DNA damage===

In each cell of the human body, the human genome experiences, on average, tens of thousands of [[DNA damage (naturally occurring)|DNA damages]] per day.<ref name = Jackson2009>{{cite journal |vauthors=Jackson SP, Bartek J |title=The DNA-damage response in human biology and disease |journal=Nature |volume=461 |issue=7267 |pages=1071–8 |date=October 2009 |pmid=19847258 |pmc=2906700 |doi=10.1038/nature08467 |url=}}</ref>  These damages can block genome replication or genome transcription, and if they are not [[DNA repair|repaired]] or are repaired incorrectly, they may lead to [[mutation]]s, or other genome alterations in the human genome that threaten cell viability.<ref name = Jackson2009/>