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The Drifting Human Genome

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The Drifting Human Genome COMMENTARY The drifting human genome Jianzhi Zhang* Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109 round the time of the comple- more, they found a normal distribution and Old World monkeys because of the tion of the draft human ge- of gene copy number among human in- inactivation of TRPC2, a crucial channel nome sequence, biologists dividuals, with a standard deviation of protein gene, in the common ancestor of heatedly debated the number 54. Between any two individuals, the hominoids and Old World monkeys (9). Aof genes contained in the human ge- average gene copy number difference is Nozawa et al. (2) further extended nome. In 2003, GeneSweep, an informal as high as 61.5. When Africans, Asians, their analysis from within populations to gene-count betting pool that began at and Europeans were analyzed sepa- between populations and between spe- the 2000 Cold Spring Harbor Labora- rately, Africans showed greater variation cies. This type of analysis is in principle tory Genome Meeting, announced Lee than Asians and Europeans, consistent similar to the Hudson–Kreitman– Rowen of the Institute of Systems Biol- with the out-of-Africa model of modern Aguade´ (HKA) test of neutrality of sin- ogy in Seattle to be the winner. His bet human origins. gle nucleotide changes (10). The HKA (25,946) was the lowest and was closest Their subsequent analysis focused on test compares the ratios of the intraspe- to what many computer programs pre- three families of chemosensory genes cific polymorphism level and the inter- dicted from the then draft human ge- that encode odorant receptors (ORs), specific divergence level between two nome sequence (1). But, in this issue of type 1 vomeronasal (pheromone) recep- loci, which are expected to be identical PNAS, Nozawa, Kawahara, and Nei (2) tors (V1Rs), and bitter taste receptors under neutrality. When one of the loci tell us that asking about the exact num- (T2Rs), respectively, because chemosen- is a functional gene and the other is a ber of human genes is meaningless, be- sory genes have particularly high levels cause different human individuals have pseudogene, rejection of the null hy- different numbers of genes, and it is not pothesis by the HKA test suggests non- uncommon for one person to have 100 It is not uncommon for neutral evolution of the functional gene, more gene copies than another person. caused by positive or negative selection. They argue that this large variation re- one person to have 100 Nozawa et al. measured the intraspecific flects genomic drift, random changes of polymorphism of OR gene copy number gene copy number in evolution. more gene copies than by its standard deviation among human Genetic variation among humans individuals and measured the interspe- takes many forms. In the past two de- another person. cific divergence of OR gene copy num- cades, most studies have focused on ber by the absolute difference in OR single-nucleotide polymorphisms. For gene number between the reference ge- example, the International HapMap of CNV (2, 4, 8). It is important to note nome sequences of humans and chim- Consortium recently published HapMap panzees. Similar measures were used for Ͼ that chemosensation is apparently im- II, which characterizes 3 million portant and highly refined in mammals, OR pseudogenes. However, they did not single-nucleotide polymorphisms geno- as Ͼ5% of all genes in a mammalian formally test the neutral hypothesis, pre- typed in 270 individuals from four hu- genome are devoted to the detection of sumably because it is not possible to man populations of African, Asian, and odorants, pheromones, and tastants. The compare polymorphism and divergence European origins (3). In the last few most interesting analysis Nozawa et al. statistically when one is measured by years, multiple groups reported a high (2) conducted is a comparison of CNV standard deviation and the other is mea- prevalence of copy number variation between functional and nonfunctional sured by difference. Inspired by their (CNV) of DNA segments ranging in size attempt, I designed a neutrality test in from 103 to 106 nucleotides in humans chemosensory genes. They found that the proportion of genes that have CNV which polymorphism is measured by the (4, 5), chimpanzees (6), and mice (7). number of OR loci that show CNV and CNV is generated by segmental duplica- is not significantly different between functional and nonfunctional OR genes. divergence is measured by the difference tion and deletion mutations that are ap- in OR gene number between the refer- parently quite frequent. Thanks to the Furthermore, the distribution of OR ence genome sequences of humans and rapid advance of genomic technologies, gene copy number among human indi- chimpanzees. Although some informa- genome-wide human CNV data recently viduals is normal for both functional tion about the intraspecific variation is became available, but studies of CNV genes and pseudogenes, with almost have been largely descriptive. The work identical standard deviations. Because lost in this treatment as the quantitative of Nozawa et al. (2) puts CNV into the pseudogenes are not subject to natural level of CNV at each locus is not con- framework of population and evolution- selection, the simplest explanation of sidered, I can now compare polymor- ary genetics and is thus an exciting ad- this observation is that the CNV of phism and divergence directly. As shown vance in our understanding of CNV in functional OR genes is also neutral. in Table 1, the null hypothesis that OR the human genome. Similar results were found for T2Rs, but gene number variation is neutral cannot 2 Nozawa et al. (2) analyzed a large the correspondence between functional be rejected (␹ ϭ 2.06, P ϭ 0.15), al- dataset of human CNV that was based genes and pseudogenes is less impressive though the functional gene copy number on a survey of the 270 HapMap individ- because the T2R family is much smaller uals (4). The dataset included 1,447 than the OR family. For V1Rs, the au- CNV regions across the human genome thors rightly treated all intact and Author contributions: J.Z. wrote the paper. (4), containing 3,144 annotated genes disrupted genes as nonfunctional gene The author declares no conflict of interest. (2). Nozawa et al. found that on aver- relics because the vomeronasal signal See companion article on page 20421. age, individuals differ from a reference transduction pathway was destroyed in *E-mail: [email protected]. individual at 277 CNV loci. Further- all hominoids (i.e., humans and apes) © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0710524104 PNAS ͉ December 18, 2007 ͉ vol. 104 ͉ no. 51 ͉ 20147–20148 Table 1. Testing the hypothesis of neutral variation of the number of odorant tion of the interspecific divergence in receptor genes sensory gene number reflects adapta- No. of genes with CNV Gene no. difference between tion, whereas the remaining fraction is Genes in humans humans and chimpanzees neutral. Although it is difficult to assess the size of each fraction at this time, the Functional 116 16 neutral fraction is likely much higher in Pseudogenes 143 11 humans than in some other mammals Data are from ref. 2. ␹2 ϭ 2.06, P ϭ 0.15. that rely heavily on chemosensation. Beyond the focus on CNV at chemo- sensory loci, the high level of CNV for difference between species appears to vious study (12) showed that purifying many genes across the human genome be larger than the neutral expectation. selection on human T2R bitter receptor demonstrates the neutrality or near neu- The findings of Nozawa et al. (2) and genes appears to have been completely trality of CNV at many loci, and the above neutrality test suggest that relaxed. Thus, even if the various copies genomic drift apparently occurs. How- both intraspecific variation and interspe- of a given chemosensory gene are ever, both disease-causing CNV (5) and cific divergence of gene copy number in slightly different in function, the fitness beneficial CNV (21) have been re- human OR and other chemosensory re- consequence in humans is expectedly to ported, so this type of genetic variation ceptor families are simply due to be extremely small. is not entirely neutral in humans. Under chance. For two reasons, this result is Would the result be different had the background of neutral CNV, identi- not unexpected. First, for intraspecific Nozawa et al. (2) studied other mam- fication of such nonneutral human CNV CNV, the proteins encoded by various mals such as mice? The answer is proba- will enhance our understanding of the copies of the same gene are likely to be bly yes. Many studies showed that the genetic basis of disease as well as adap- extremely similar in sequence and func- numbers of T2R, OR, V1R, and V2R tation. Although genome-wide identifi- tion because of very recent divergences (type 2 vomeronasal receptor) genes cation of CNV is rather crude at of the different copies. Because dosage vary dramatically across mammals and present, because the breakpoints of each is unlikely to be important to chemosen- that this variation is among the largest copy and the copy number difference sory receptors, the actual copy number of all mammalian gene families exam- between two individuals at each locus of each sensory gene should not affect ined (13–19). For example, of those are not precisely determined, the impli- the fitness of an individual as long as at mammals that have an intact vomerona- cations of CNV polymorphism and least one copy is present in the individ- sal system, platypus has 270 functional ual. Second, olfaction is believed to play V1R genes, whereas the dog has only 8 divergence can be reconfirmed and a less important role in humans than in (15).
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