Recent evolution of the mutation rate and spectrum in ... · Annu. Rev. Genom. Human Genet. 2014.15. Downloaded from by University of California - Berkeley on 08/30/14. For personal

Recent evolution of the mutation rate andspectrum in Europeans

Kelley HarrisBay Area Population Genomics Meeting XI

University of California Berkeley

Kelley Harris ([email protected]) Recent mutation spectrum evolution in Europeans

What is the human mutation rate?

GG15CH03-Przeworski ARI 31 May 2014 13:44

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Conrad et al.2011

Kong et al. 2012

Campbell et al.2012

Michaelson et al. 2012Jiang et al. 2013

Neale et al. 2012

O'Roak et al. 2012

Sanders et al. 2012 (controls)

Sanders et al.2012 (cases)

Iossifov et al. 2012

Zaidi et al.2013 (cases)

Zaidi et al.2013 (controls)

Fromer et al.2014

Xue et al. 2009Wang et al. 2012

Awadalla et al. 2010

Kondrashov 2003

Lynch 2010b

Chimpanzee Seq.Anal. Consort. 2005

Chimpanzee Seq.Anal. Consort. 2005Nachman & Crowell 2000

20 25 30 35 40 45Mean paternal age

Kong et al. 2012

Campbell et al. 2012 Michaelson et al.2012

Jiang et al. 2013

Neale et al. 2012

O'Roak et al. 2012

Sanders et al. 2012 (controls)

Sanders et al. 2012 (cases)

Iossifov et al. 2012

Zaidi et al. 2013 (cases)Zaidi et al. 2013 (controls)

Fromer et al. 2014

Wang et al. 2012

Exome

Roach et al. 2010

Figure 1Estimates of the human mutation rate per base pair per generation. Plotted are estimates of (a) the human mutation rate estimatedusing different approaches and (b) the human mutation rate as a function of the mean paternal age for the studies where those data wereavailable. Colored horizontal lines indicate the average mutation rate within each study type. We calculated a phylogenetic mutationrate based on a human–chimpanzee genetic divergence of 1.23% (23, 24, 36), a human–chimpanzee divergence time (i.e., time to themost recent common ancestor) of 7 million years, and a sex-averaged generation time of 25 years (43). The Nachman & Crowell (111)estimate is based on nucleotide substitutions only and is provided under their assumptions (a divergence time of 5.4 million years and ageneration time of 20 years). To be consistent among studies, we calculated the paternal age at birth (by adding nine months asappropriate when studies reported the paternal age at conception). The Michaelson et al. (103) estimate has been revised to take intoaccount the false-negative rate reported by the authors. The Jiang et al. (71) estimate was not reported by the authors; instead, weobtained it from their counts using the denominator and the false-positive and false-negative rates from Michaelson et al. (103), who hada very similar study design. Conrad et al. (25) measured the mutation rate in a European (CEU) trio and Yoruban (YRI) trio separately;we plotted the average. Sanders et al. (141) sequenced the exomes of autistic probands (cases) as well as unaffected siblings (controls).Iossifov et al. (70) sequenced the exomes of autistic probands and their unaffected siblings but reported the combined mutation rate (nosignificant difference was found). Zaidi et al. (175) sequenced individuals with congenital heart disease (cases) and unrelated individuals(controls). Mutation rates for exome studies were not adjusted for error rates, as the false-negative rate was not consistently reportedand most studies validated all de novo mutations. “Other partial” refers to studies that sequenced targeted regions or other subsets ofthe genome. Xue et al. (171) sequenced the Y chromosomes of two individuals separated by 13 generations, and Wang et al. (162)sequenced eight sperm from a single individual. Kondrashov (79) and Lynch (96) calculated the mutation rate from disease incidences.

Drosophila melanogaster (72). More cases are expected as families of more than one offspring aresequenced.

THE AVERAGE MUTATION RATE AND INTERINDIVIDUALVARIATION

The Number of De Novo Mutations Inherited by Humans

Whole genome pedigree-based estimates yield a mutation rate of 10!8 per base pair per generation.This is about two-thirds of the rate estimated by exome sequencing (Figure 1a), consistent witha more than threefold enrichment of CpGs in exons compared with the rest of the genomeas well as with their 20% higher GC content (115). Perplexingly, however, the mutation rateestimated by whole-genome pedigree studies is also more than twofold below the rates obtainedfrom phylogenetic approaches (142) (Figure 1a), even though it might be expected, if anything,to be slightly higher (because it includes deleterious mutations that would eventually be weededout by selection).

www.annualreviews.org • Variation in Human Germline Mutation 19.7

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Segurel, Wyman and Przeworski Annu Rev Genom Human Genet 2014


9

REVIEW ARTICLES

BioEssays Vol. 3, No. 1

30 20

Rates of Molecular Evolution : The

I B A

Hominoid Slowdown Morris Goodman

- Ceboidea

Aves E lasrnobranchi i

Summary It is proposed that early in phylogeny a large proportion of amino acid substitutions were selectively neutral, but that bursts of adaptive substitutions during major radiations of life so increased selective constraints that most mutations in modern proteins are detrimental. Recent findings on D N A nucleotide sequences indicate that decreasing rnuta- tion rates further slowed the rate of molecular evolution in the lineage to humans.

An Hypothesis on Neutral Mutations and Slowing Rates Over twenty years ago the idea was put forward that molecular evolution slowed in the primate lineage which led to Recent findings indicate that this is the case for amino acid replacements in proteins5, and for base substitutions in both noncoding and coding DNA7-l0 The original findings that suggested the hominoid slowdown idea were immunological. Almost no antigenic divergencies were found throughout the whole ape superfamily Hominoidea on comparing human (Homo), chimpanzee (Pan), gorilla (Gorilla), orangutan (Pongo), and gibbon (Hylobates) serum albumins, whereas marked albumin divergencies were evident within the ungulate family Bovidae - even within the subfamily B~vinae.'-~ Moreover, for a range of serum proteins, humans showed only small antigenic differences from orang- utans and gibbons and, at most, trace differences from gorillas and chimpan- zees. Thus, considering the seemingly large amount of morphological evolution in the Hominoidea indicated by tra- ditional taxonomic schemes that divide this superfamily into families Homini- dae, Pongidae, and Hylobatidae, the amount of protein evolution dis- tinguishing humans from other hominoids appeared to be surprisingly small.

An hypothesis was proposed', in which a slowdown of rates of protein evolution in the Hominoidea was the culmination of a long-term phylogenetic

trend extending from the time of the origin of proteins to the present. This hypothesis, pre-dating the neutralist views of Kimura," postulated that early in phylogeny most amino acid replacements in proteins were selectively neutral. However, a small fraction of substitutions were adaptive and their accumulation over geological epochs, by shaping dense arrays of lock-and-key interaction sites on proteins, increased the number of selective constraints that cause most mutations in modern proteins to be detrimental. The slowdown in rates resulted from proteins having fewer sites where selectively neutral mutations could accumulate.

In essence, the slowdown hypothesis proposed that over eons of time natural selection increased the internal complexity of life and, in safeguarding the new and complex functions that had evolved, slowed the rate of molecular evolution. On noting that an unrivaled increase in nervous system complexity occurred in the primate lineage to

humans, the advance in brain evolution was related to lengthening generation and gestation times and to evolution of the hemochorial placenta. Compared to earlier epitheliochorial placentas, the higher primate hemochorial placenta allowed for the efficient maternal-to- fetal transfer of nutrients and oxygen needed by the enlarging cerebral cortex of the developing primate fetus. In turn, maternal immunological selection against deviant fetal isoantigens could then have become an additional factor slowing the rate of protein evolution in the H~minoidea.'-~

Irrespective of whether or not maternal isoimmunizations had a significant braking effect on the hominoid rate of molecular evolution, the slowdown hypothesis extended to the realm of DNA predicts that rate decelerations should be especially evident in the Hominoidea. The key premise is that a majority of genomic DNA sequence changes are neutral changes having little or no effect on the phenotype.'O Thus

Ceboidea Erinaceoidea p Hemoglobin -

Aves Rates of -.I"..."I. "

J Homo ascent to I Homo ~ z o i d e a - Erinaceoidea a Hemoglobin

Aves

NR%

Millions of years before present

Homo

FCeboidea Chiroptera

Cytochrome C fl Pan

Elasmobranchii

0 5 0 Number of NR

Fig. 1. Acceleration-deceleration pattern in rates of sequence evolution. The portions of the globin and cytochrome c genealogical trees5 shown depict the phyletic line to Homo from the early vertebrates to the present. The length of each branch equals the number of nucleotide replacements that caused amino acid changes, calculated to have occurredalong that line of evolution, with the main branches shown being those that circumscribe the accelerated evolution depicted in the bar graph between the vertebrate and bird-mammal ancestors and again between the Eutheria and Anthropoidea ancestors.

BioEssays Vol. 3, No. 1 13

REVIEW ARTICLES

WI monkey

0 10 20 30 40 50 60 70 80 90 100110120 130140150 160107 180 Number of nucleotide substitutions

Fig. 5. Evidence that among higher primates, at the genetic DNA sequence level, the phyletic line to humans changed the least in descent from the Anthropoidea ancestor to the present. This evidence comes from the phylogenetic reconstruction carried out by the maximum parsimony method, using the available nucleotide sequence data on the 7-globin genetic locus.a This locus, which is an uctive embryonicully expressed gene in goats, became a non-expressedpsordogene in the early primates. The length of each branch is the number of genic changes calculated to have occurred along thut line of evolution.

parison of these gorilla sequences to the corresponding G y and *y human genes extended the observation of an un- usually slow evolutionary rate, already known from hominid amino acid sequence^,^, to silent or synonymous substitutions in the y-coding regions. Not even one silent substitution was found for either G y or Ay genes (as illustrated in Fig. 4 for gorilla and human Gy sequences), although the average rate of mammalian globin genes would have yielded at least nine substitutions over the time period involved.

Including in the analysis the recently sequenced chimpanzee Gy and Ay genes, as well as cDNA sequences for coding regions of the two non-allelic chimpanzee u-globin loci, confirms that a marked deceleration of rates of sequence evolution occurred in descent of the homininesZ6 The analysis revealed an 1 %fold decrease in the non-synonymous (amino acid changing) rate and a 7.5- fold decrease in the synonymous rate in descent from early eutherians to ex- tant hominines. The non-synonymous rate foundz6 for hominines, 0.1 x substitutions per site per year, is a ninth of the average rate found30 for 39 mammalian genes in inter-ordinal com- parisons; also a ninth of the average for globin genes (a, B, y, and /3) during descent of the four mammalian orders (Primates, Lagomorpha, Artiodactyla, and Rodentia) represented by sequenced hemoglobin 26 The synonymous rate found for hominines, 0.9 x lo9 substitutions per site per year, is about a fifth of the rate for the 39 mammalian genes and a third to a fourth of the rate for globin genes during descent of the four eutherian orders.

The results8 on the primate pseudo- gene between y and S loci also point to a slowdown in DNA sequence evolution in human descent. Phylogenetic recon-

structions by the parsimony method have shown that this primate pseudo- gene locus (labelled 97) is the ortho- logue of an embryonically expressed goat /I-globin (labelled q) and that the expressed 7-globin gene of early eutherians became the yhpglobin pseudo- gene in basal primates.s The s-@q locus evolved at the rate of 2.4 x substitutions per site per year for the first 40 or so million years of descent from the eutherian (goat/primate) ancestor to the Anthropoidea (owl monkey/hominoid) ancestor and for the last 40 million years in descent to humans at the re- duced rate of I . 1 x lo+, which is about a fifth of the neutral rate30 found for mammalian pseudogenes. In contrast to the sharp deceleration of the hominoid rate, the prosimian lemur and New World owl monkey $71 rates were found to resemble the early primate rate.* The much slower qhj evolution in hominoids than in owl monkey is depicted in Fig. 5.

The analysis of Wu and Li9 on human and mouse globin genes (a, E, y, and @) and nine other kinds of human and rodent genes supports the trends seen in the above findings and clearly establishes that synonymous substitutions accum- ulated at a much faster rate in the rodent lineage than in the human lineage since their divergence (an average of twice as fast over the long time-spans involved). The explanation offered for the higher rate of molecular evolution in rodents is that rodents have shorter generation times and thus higher mutation rates. Their explanation is com- patible with the proposal that a slowdown in rate occurred in human descent because of lengthening generation times.

Britten,lo from his analysis of pub- lished measurements of DNA sequence divergence between taxa, also supports

the slowdown hypothesis. He finds that rates of DNA sequence evolution vary by a factor of five among different phylogenetic groups, higher primates and some bird lineages showing the slowest and rodents, sea urchins, and Drosophila showing the fastest rates. Britten concludes that the rate of DNA sequence evolution decreased markedly during primate phylogeny in the lineage to hominoids and singles out the possibility that selection of more efficient mechanisms of DNA repair could have caused the retardation in rates of higher primate DNA evolution.

I thank Wen-Hsuing Li and Roy J. Britten for providing me with papers before publication. My research is supported by NSF grant BSR 83-07336.

REFERENCES 1 GOODMAN,M. (1961). The role of im- munochemical differences in the phyletic development of human behavior. Hum. Biol.

2 GOODMAN, M. (1962). Evolution of the immunologic species specificity of human serum proteins. Hum. Biol. 34, 104150. 3 GOODMAN, M. (1 962). Immunochemistry of the Primates and primate evolution. Ann. N . Y. Acad. Sci. 102, 219-234. 4 GOODMAN, M. (1963). Man's place in the phylogeny of the Primates as reflected in serum proteins. In Class$cation and Human Evolution(ed. S . L. Washburn), pp. 204-234. Aldine Press, Chicago. 5 GOODMAN, M. (1981). Decoding the pattern of protein evolution. Progr. Biophys. MoI. Biol. 37, 105-164. 6 GOODMAN, M., BRAUNITZER, G., STANGL, A. & SCHRANK,B. (1983). Evidence on human origins from haemoglobins of African apes. Nature. 303, 546-548. 7 SCOTT, A. F., HEATH, P., TRUSKO, S . , BOYER, S . H., PRASS, W., GOODMAN, M., CZELUSNIAK, J., CHANG, L.-Y. E. & SLIGHTOM, J. L. (1984). The sequence of the gorilla fetal globin genes: evidence for multiple gene conversions in human evolution. Mol. Biol. Evol. 1, 371-389. 8 GOODMAN, M., KOOP, B. F., CZELUSNIAK, J., WEISS, M. L. & SLIGHTOM, J. L. (1984). The g-globin gene: its long evolutionary history in the /I-globin gene family of mammals. J. Mol. Biol. 180, 803-823. 9 Wu, C.-I. & LI, W.-H. (1985). Evidence for higher rates of nucleotide substitutions in rodents than in man. Proc. Natl. Acad. Sci.

10 BRITTEN, R. J. (1985). Rates of DNA sequence evolution differ between taxonomic groups. Science (submitted). 11 KIMURA, M. (1968). Evolutionary rate at the molecular level. Nulure. 217, 624-626. 12 CLOUD, P. (1978). Cosmos, Earth, and Man. Yale University Press, New Haven. 13 HART, R. & SETLOW, R . B . (1974). Correlation between deoxyribonucleic acid

33, 131-162.

USA. 82, 1741-1745.

Goodman BioEssays 1985

© 1987 Nature Publishing Group

Li and Tanimura Nature 1987

Scally and Durbin Nature Rev Genet 2012


9

REVIEW ARTICLES

BioEssays Vol. 3, No. 1

30 20

Rates of Molecular Evolution : The

I B A

Hominoid Slowdown Morris Goodman

- Ceboidea

Aves E lasrnobranchi i

Summary It is proposed that early in phylogeny a large proportion of amino acid substitutions were selectively neutral, but that bursts of adaptive substitutions during major radiations of life so increased selective constraints that most mutations in modern proteins are detrimental. Recent findings on D N A nucleotide sequences indicate that decreasing rnuta- tion rates further slowed the rate of molecular evolution in the lineage to humans.

An Hypothesis on Neutral Mutations and Slowing Rates Over twenty years ago the idea was put forward that molecular evolution slowed in the primate lineage which led to Recent findings indicate that this is the case for amino acid replacements in proteins5, and for base substitutions in both noncoding and coding DNA7-l0 The original findings that suggested the hominoid slowdown idea were immunological. Almost no antigenic divergencies were found throughout the whole ape superfamily Hominoidea on comparing human (Homo), chimpanzee (Pan), gorilla (Gorilla), orangutan (Pongo), and gibbon (Hylobates) serum albumins, whereas marked albumin divergencies were evident within the ungulate family Bovidae - even within the subfamily B~vinae.'-~ Moreover, for a range of serum proteins, humans showed only small antigenic differences from orang- utans and gibbons and, at most, trace differences from gorillas and chimpan- zees. Thus, considering the seemingly large amount of morphological evolution in the Hominoidea indicated by tra- ditional taxonomic schemes that divide this superfamily into families Homini- dae, Pongidae, and Hylobatidae, the amount of protein evolution dis- tinguishing humans from other hominoids appeared to be surprisingly small.

An hypothesis was proposed', in which a slowdown of rates of protein evolution in the Hominoidea was the culmination of a long-term phylogenetic

trend extending from the time of the origin of proteins to the present. This hypothesis, pre-dating the neutralist views of Kimura," postulated that early in phylogeny most amino acid replacements in proteins were selectively neutral. However, a small fraction of substitutions were adaptive and their accumulation over geological epochs, by shaping dense arrays of lock-and-key interaction sites on proteins, increased the number of selective constraints that cause most mutations in modern proteins to be detrimental. The slowdown in rates resulted from proteins having fewer sites where selectively neutral mutations could accumulate.

In essence, the slowdown hypothesis proposed that over eons of time natural selection increased the internal complexity of life and, in safeguarding the new and complex functions that had evolved, slowed the rate of molecular evolution. On noting that an unrivaled increase in nervous system complexity occurred in the primate lineage to

humans, the advance in brain evolution was related to lengthening generation and gestation times and to evolution of the hemochorial placenta. Compared to earlier epitheliochorial placentas, the higher primate hemochorial placenta allowed for the efficient maternal-to- fetal transfer of nutrients and oxygen needed by the enlarging cerebral cortex of the developing primate fetus. In turn, maternal immunological selection against deviant fetal isoantigens could then have become an additional factor slowing the rate of protein evolution in the H~minoidea.'-~

Irrespective of whether or not maternal isoimmunizations had a significant braking effect on the hominoid rate of molecular evolution, the slowdown hypothesis extended to the realm of DNA predicts that rate decelerations should be especially evident in the Hominoidea. The key premise is that a majority of genomic DNA sequence changes are neutral changes having little or no effect on the phenotype.'O Thus

Ceboidea Erinaceoidea p Hemoglobin -

Aves Rates of -.I"..."I. "

J Homo ascent to I Homo ~ z o i d e a - Erinaceoidea a Hemoglobin

Aves

NR%

Millions of years before present

Homo

FCeboidea Chiroptera

Cytochrome C fl Pan

Elasmobranchii

0 5 0 Number of NR

Fig. 1. Acceleration-deceleration pattern in rates of sequence evolution. The portions of the globin and cytochrome c genealogical trees5 shown depict the phyletic line to Homo from the early vertebrates to the present. The length of each branch equals the number of nucleotide replacements that caused amino acid changes, calculated to have occurredalong that line of evolution, with the main branches shown being those that circumscribe the accelerated evolution depicted in the bar graph between the vertebrate and bird-mammal ancestors and again between the Eutheria and Anthropoidea ancestors.

BioEssays Vol. 3, No. 1 13

REVIEW ARTICLES

WI monkey

0 10 20 30 40 50 60 70 80 90 100110120 130140150 160107 180 Number of nucleotide substitutions

Fig. 5. Evidence that among higher primates, at the genetic DNA sequence level, the phyletic line to humans changed the least in descent from the Anthropoidea ancestor to the present. This evidence comes from the phylogenetic reconstruction carried out by the maximum parsimony method, using the available nucleotide sequence data on the 7-globin genetic locus.a This locus, which is an uctive embryonicully expressed gene in goats, became a non-expressedpsordogene in the early primates. The length of each branch is the number of genic changes calculated to have occurred along thut line of evolution.

parison of these gorilla sequences to the corresponding G y and *y human genes extended the observation of an un- usually slow evolutionary rate, already known from hominid amino acid sequence^,^, to silent or synonymous substitutions in the y-coding regions. Not even one silent substitution was found for either G y or Ay genes (as illustrated in Fig. 4 for gorilla and human Gy sequences), although the average rate of mammalian globin genes would have yielded at least nine substitutions over the time period involved.

Including in the analysis the recently sequenced chimpanzee Gy and Ay genes, as well as cDNA sequences for coding regions of the two non-allelic chimpanzee u-globin loci, confirms that a marked deceleration of rates of sequence evolution occurred in descent of the homininesZ6 The analysis revealed an 1 %fold decrease in the non-synonymous (amino acid changing) rate and a 7.5- fold decrease in the synonymous rate in descent from early eutherians to ex- tant hominines. The non-synonymous rate foundz6 for hominines, 0.1 x substitutions per site per year, is a ninth of the average rate found30 for 39 mammalian genes in inter-ordinal com- parisons; also a ninth of the average for globin genes (a, B, y, and /3) during descent of the four mammalian orders (Primates, Lagomorpha, Artiodactyla, and Rodentia) represented by sequenced hemoglobin 26 The synonymous rate found for hominines, 0.9 x lo9 substitutions per site per year, is about a fifth of the rate for the 39 mammalian genes and a third to a fourth of the rate for globin genes during descent of the four eutherian orders.

The results8 on the primate pseudo- gene between y and S loci also point to a slowdown in DNA sequence evolution in human descent. Phylogenetic recon-

structions by the parsimony method have shown that this primate pseudo- gene locus (labelled 97) is the ortho- logue of an embryonically expressed goat /I-globin (labelled q) and that the expressed 7-globin gene of early eutherians became the yhpglobin pseudo- gene in basal primates.s The s-@q locus evolved at the rate of 2.4 x substitutions per site per year for the first 40 or so million years of descent from the eutherian (goat/primate) ancestor to the Anthropoidea (owl monkey/hominoid) ancestor and for the last 40 million years in descent to humans at the re- duced rate of I . 1 x lo+, which is about a fifth of the neutral rate30 found for mammalian pseudogenes. In contrast to the sharp deceleration of the hominoid rate, the prosimian lemur and New World owl monkey $71 rates were found to resemble the early primate rate.* The much slower qhj evolution in hominoids than in owl monkey is depicted in Fig. 5.

The analysis of Wu and Li9 on human and mouse globin genes (a, E, y, and @) and nine other kinds of human and rodent genes supports the trends seen in the above findings and clearly establishes that synonymous substitutions accum- ulated at a much faster rate in the rodent lineage than in the human lineage since their divergence (an average of twice as fast over the long time-spans involved). The explanation offered for the higher rate of molecular evolution in rodents is that rodents have shorter generation times and thus higher mutation rates. Their explanation is com- patible with the proposal that a slowdown in rate occurred in human descent because of lengthening generation times.

Britten,lo from his analysis of pub- lished measurements of DNA sequence divergence between taxa, also supports

the slowdown hypothesis. He finds that rates of DNA sequence evolution vary by a factor of five among different phylogenetic groups, higher primates and some bird lineages showing the slowest and rodents, sea urchins, and Drosophila showing the fastest rates. Britten concludes that the rate of DNA sequence evolution decreased markedly during primate phylogeny in the lineage to hominoids and singles out the possibility that selection of more efficient mechanisms of DNA repair could have caused the retardation in rates of higher primate DNA evolution.

I thank Wen-Hsuing Li and Roy J. Britten for providing me with papers before publication. My research is supported by NSF grant BSR 83-07336.

REFERENCES 1 GOODMAN,M. (1961). The role of im- munochemical differences in the phyletic development of human behavior. Hum. Biol.

2 GOODMAN, M. (1962). Evolution of the immunologic species specificity of human serum proteins. Hum. Biol. 34, 104150. 3 GOODMAN, M. (1 962). Immunochemistry of the Primates and primate evolution. Ann. N . Y. Acad. Sci. 102, 219-234. 4 GOODMAN, M. (1963). Man's place in the phylogeny of the Primates as reflected in serum proteins. In Class$cation and Human Evolution(ed. S . L. Washburn), pp. 204-234. Aldine Press, Chicago. 5 GOODMAN, M. (1981). Decoding the pattern of protein evolution. Progr. Biophys. MoI. Biol. 37, 105-164. 6 GOODMAN, M., BRAUNITZER, G., STANGL, A. & SCHRANK,B. (1983). Evidence on human origins from haemoglobins of African apes. Nature. 303, 546-548. 7 SCOTT, A. F., HEATH, P., TRUSKO, S . , BOYER, S . H., PRASS, W., GOODMAN, M., CZELUSNIAK, J., CHANG, L.-Y. E. & SLIGHTOM, J. L. (1984). The sequence of the gorilla fetal globin genes: evidence for multiple gene conversions in human evolution. Mol. Biol. Evol. 1, 371-389. 8 GOODMAN, M., KOOP, B. F., CZELUSNIAK, J., WEISS, M. L. & SLIGHTOM, J. L. (1984). The g-globin gene: its long evolutionary history in the /I-globin gene family of mammals. J. Mol. Biol. 180, 803-823. 9 Wu, C.-I. & LI, W.-H. (1985). Evidence for higher rates of nucleotide substitutions in rodents than in man. Proc. Natl. Acad. Sci.

10 BRITTEN, R. J. (1985). Rates of DNA sequence evolution differ between taxonomic groups. Science (submitted). 11 KIMURA, M. (1968). Evolutionary rate at the molecular level. Nulure. 217, 624-626. 12 CLOUD, P. (1978). Cosmos, Earth, and Man. Yale University Press, New Haven. 13 HART, R. & SETLOW, R . B . (1974). Correlation between deoxyribonucleic acid

33, 131-162.

USA. 82, 1741-1745.

Goodman BioEssays 1985

© 1987 Nature Publishing Group

Li and Tanimura Nature 1987

Scally and Durbin Nature Rev Genet 2012


The Hominoid Slowdown: Potential Causes

1. Changes in biochemistry of DNA replication/ repairBritten Science 1986

2. Lengthening generation time Li and Tanimura Nature 1987

Kong et al. Nature 2012












Revisiting the DNA replication/repair hypothesis

I Exposure to mutagenic UV is extremely variable outside Africa

Jablonski and Chaplin PNAS 2010

I DNA damage response pathways show evidence of local geneexpression adaptation in humans Fraser Genome Res 2013


Revisiting the DNA replication/repair hypothesis

I Exposure to mutagenic UV is extremely variable outside Africa

Jablonski and Chaplin PNAS 2010

I DNA damage response pathways show evidence of local geneexpression adaptation in humans Fraser Genome Res 2013


Looking for evidence of changing DNA damage/repairbiochemistry in the 1000 Genomes Phase I data

I Private European mutations := Derived allele present inEurope and absent from any Asians/Africans

I May be present or absent in admixed American populations

I Use strict imputation quality filter (RSQ>0.95) to avoidmisclassifying shared variants as private

I χ2 test for differences among variants private to Europe, Asia,and Africa




















Mutation spectra of continent-private variation

1.9e-174

7.1e-218 TCCGGA

A. Europe v. Africa

0.4 0.2 0.0 0.2 0.4Fold excess in Europe

1.0

3.7e-06

1.4e-11

5.2e-17

1.9e-22

7.2e-28

2.7e-33

1.0e-38

3.7e-44

P v

alue

ACC

CCC

TCT

AGA

AGC

GGG

GGT

TTAATT

0.4 0.2 0.0 0.2 0.4Fold excess in Asia

AAAAAT

AAA

AAC

AAT

TAC TATACCACTATA

ATTTTATTT

ATT

A→C T→GA→G T→CA→T T→AC→A G→TC→G G→CC→T G→A

B. Asia v. Africa

Harris, in revision.

The rate of TCC→TTC transitions appears to have recentlyincreased in Europe


Mutation spectra of continent-private variation

1.9e-174

7.1e-218 TCCGGA

A. Europe v. Africa

0.4 0.2 0.0 0.2 0.4Fold excess in Europe

1.0

3.7e-06

1.4e-11

5.2e-17

1.9e-22

7.2e-28

2.7e-33

1.0e-38

3.7e-44

P v

alue

ACC

CCC

TCT

AGA

AGC

GGG

GGT

TTAATT

0.4 0.2 0.0 0.2 0.4Fold excess in Asia

AAAAAT

AAA

AAC

AAT

TAC TATACCACTATA

ATTTTATTT

ATT

A→C T→GA→G T→CA→T T→AC→A G→TC→G G→CC→T G→A

B. Asia v. Africa


The rate of TCC→TTC transitions appears to have recentlyincreased in Europe


Result is reproducible with Complete Genomics data

Complete Genomics42 genomes


Subsampled 42 genomesfrom 1000 Genomes Phase I


Result is reproducible with Complete Genomics data

Complete Genomics42 genomes


Subsampled 42 genomesfrom 1000 Genomes Phase I


Admixed populations have intermediate TCC→TTC frequencies

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Eur

opea

n

Briti

sh

Finn

ish0.015

0.020

0.025

0.030

0.035

0.040



Gradient of Asian ancestry in Europe

16000 18000 20000 22000 24000 26000 28000European/Asian shared derived variants (dPAsE)

0.028

0.030

0.032

0.034

0.036

0.038f(

TCC)

(Priv

ate

Euro

pean

var

iant

s)ItalianSpanishCentral EuropeanBritishFinnish



0.00 0.01 0.02 0.03 0.04 0.05Private derived allele frequency

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

0.040

TCC→

TTC

frequ

ency

Europe Africa Asia



Differences in transcriptional strand bias

I TCC→TTC is not equivalent to reverse complementGGA→GAA in transcribed regions

I Transcription-coupled repair corrects damage affecting thetranscribed DNA strand

medical-dictionary.com



I TCC→TTC is not equivalent to reverse complementGGA→GAA in transcribed regions

I Transcription-coupled repair corrects damage affecting thetranscribed DNA strand

medical-dictionary.com



0.0080.0100.0120.0140.0160.0180.0200.0220.0240.0260.0280.0300.0320.034

Europe Africa Asia

intergenic TCC/GGA

total genic TCC/GGA

transcribedstrandGGA

transcribedstrandTCC

Frequency of TCC→TTC/GGA→GAA




0.0080.0100.0120.0140.0160.0180.0200.0220.0240.0260.0280.0300.0320.034

Europe Africa Asia

intergenic TCC/GGA

total genic TCC/GGA

transcribedstrandGGA

transcribedstrandTCC

Frequency of TCC→TTC/GGA→GAA



Association of TCC→TTC with UV damage in cell culture

Mutation Research, 289 (1993) 131-138 131 © 1993 Elsevier Science Publishers B.V. All rights reserved 0027-5107/93/$06.00

MUT 00814

UV-induced G" C ---> A: T transitions at the APRT locus of Chinese hamster ovary cells cluster at frequently damaged 5'-TCC-3' sequences

E.A. Drobetsky and E. Sage Institut Curie, Section de Biologie, CNRS URA 1292, 26 rue d'Ulm, 75231 Paris Cedex 05, France

(Received 11 December 1992) (Revision received 2 March 1993)

(Accepted 16 April 1993)

Keywords: Mutational specificity; Damage distribution; Ultraviolet light; DNA context; Cyclobutane pyrimidine dimers; (6-4) Pyrimidine pyrimidone photoproduct

Summary

We have determined the relative frequency in vitro of UV-induced cyclobutane pyrimidine dimers (py < > py) and (6-4) pyrimidine pyrimidone photoproducts (py(6-4)pyo) at individual sites in selected regions of the Chinese hamster ovary (CHO) adenine phosphoribosyltransferase (apr t ) gene, and compared this to the observed specificity of UV-induced mutations (Drobetsky et al., 1987, 1989). Our results indicate that G : C ~ A: T transition "hotspots" (multiple occurrences) at the chromosomal CHO aprt locus, the majority of which occur at 5'-TCC-3', are clearly targeted at sites associated with a relatively high yield of py < > py a n d / o r py(6-4)pyo. We conclude that photoproduct frequency plays a major role in UV-induced transition mutagenesis at 5'-TCC-3' sites at an endogenous locus in a rodent cell line, and that both py(6-4)pyo and py < > py have premutagenic potential.

The fixation of heritable changes in the genetic material is not a random process (Benzer, 1961). The probability that mutation will occur at a particular position in DNA following exposure to a genotoxic agent is likely to be determined by many factors, such as the distribution of premutagenic damage, the competitive efficiencies of error-free and error-prone modes of repair, a n d / o r the fidelity of translesion synthesis. These vari- ables can all be influenced by local DNA-se-

Correspondence: Dr. E.A. Drobetsky, (present address), HOpital Maisonneuve-Rosemont, 5415 Boulevard de l'As- sumption, Montr6al, Qu6bec HIT 2M4, Canada. Tel. 514-252-3400, ext. 4665; Fax 514-252-3569.

quence context effects in a mutagen-, species- and allele-specific manner. Mutational specificity studies, which characterize DNA sequence alter- ations in mutant alleles, can yield insight into these complex processes. Furthermore, the power of this type of investigation can be enhanced when information about the distribution of po- tentially premutagenic damage in the target gene is obtained concomitantly.

Most of these combined investigations have centered on 254-nm UV light, since a large mutant-sequence data base exists both in bacteria (Miller, 1985; Schaaper et al., 1987) and mammalian cells (Bredberg et al., 1986; Drobetsky et al., 1987, 1989; Hauser et al., 1986). Furthermore,

Drobetsky et al. PNAS 1987


Association of TCC→TTC with UV damage in cell culture

Mutation Research, 289 (1993) 131-138 131 © 1993 Elsevier Science Publishers B.V. All rights reserved 0027-5107/93/$06.00

MUT 00814

UV-induced G" C ---> A: T transitions at the APRT locus of Chinese hamster ovary cells cluster at frequently damaged 5'-TCC-3' sequences

E.A. Drobetsky and E. Sage Institut Curie, Section de Biologie, CNRS URA 1292, 26 rue d'Ulm, 75231 Paris Cedex 05, France

(Received 11 December 1992) (Revision received 2 March 1993)

(Accepted 16 April 1993)

Keywords: Mutational specificity; Damage distribution; Ultraviolet light; DNA context; Cyclobutane pyrimidine dimers; (6-4) Pyrimidine pyrimidone photoproduct

Summary

We have determined the relative frequency in vitro of UV-induced cyclobutane pyrimidine dimers (py < > py) and (6-4) pyrimidine pyrimidone photoproducts (py(6-4)pyo) at individual sites in selected regions of the Chinese hamster ovary (CHO) adenine phosphoribosyltransferase (apr t ) gene, and compared this to the observed specificity of UV-induced mutations (Drobetsky et al., 1987, 1989). Our results indicate that G : C ~ A: T transition "hotspots" (multiple occurrences) at the chromosomal CHO aprt locus, the majority of which occur at 5'-TCC-3', are clearly targeted at sites associated with a relatively high yield of py < > py a n d / o r py(6-4)pyo. We conclude that photoproduct frequency plays a major role in UV-induced transition mutagenesis at 5'-TCC-3' sites at an endogenous locus in a rodent cell line, and that both py(6-4)pyo and py < > py have premutagenic potential.

The fixation of heritable changes in the genetic material is not a random process (Benzer, 1961). The probability that mutation will occur at a particular position in DNA following exposure to a genotoxic agent is likely to be determined by many factors, such as the distribution of premutagenic damage, the competitive efficiencies of error-free and error-prone modes of repair, a n d / o r the fidelity of translesion synthesis. These vari- ables can all be influenced by local DNA-se-

Correspondence: Dr. E.A. Drobetsky, (present address), HOpital Maisonneuve-Rosemont, 5415 Boulevard de l'As- sumption, Montr6al, Qu6bec HIT 2M4, Canada. Tel. 514-252-3400, ext. 4665; Fax 514-252-3569.

quence context effects in a mutagen-, species- and allele-specific manner. Mutational specificity studies, which characterize DNA sequence alter- ations in mutant alleles, can yield insight into these complex processes. Furthermore, the power of this type of investigation can be enhanced when information about the distribution of po- tentially premutagenic damage in the target gene is obtained concomitantly.

Most of these combined investigations have centered on 254-nm UV light, since a large mutant-sequence data base exists both in bacteria (Miller, 1985; Schaaper et al., 1987) and mammalian cells (Bredberg et al., 1986; Drobetsky et al., 1987, 1989; Hauser et al., 1986). Furthermore,

Drobetsky et al. PNAS 1987


Association of TCC→TTC with melanoma

Alexandrov, et al. Nature 2013

I 30% of somatic melanoma mutations are TCC→TTC

I Europeans have 10–20-fold higher melanoma incidence thanAsians or AfricansCress and Holly Cancer Causes and Control 1997


Association of TCC→TTC with melanoma

Alexandrov, et al. Nature 2013

I 30% of somatic melanoma mutations are TCC→TTC

I Europeans have 10–20-fold higher melanoma incidence thanAsians or AfricansCress and Holly Cancer Causes and Control 1997


Open Questions and Future Directions

I Why does a signature of UV damage appear in the germline?

I Use young mutations in admixed genomes to map the geneticbasis of TCC→TTC acceleration

I Molecular clock unreliabilityI How variable is mutation rate within the human population?I Number and timing of recent mutation rate changes?I Implications for demographic inference










I Molecular clock unreliability

I How variable is mutation rate within the human population?I Number and timing of recent mutation rate changes?I Implications for demographic inference





I Molecular clock unreliabilityI How variable is mutation rate within the human population?

I Number and timing of recent mutation rate changes?I Implications for demographic inference





I Molecular clock unreliabilityI How variable is mutation rate within the human population?I Number and timing of recent mutation rate changes?

I Implications for demographic inference







Acknowledgements

I Rasmus Nielsen

I Elad Ziv

I David Reich

I Richard Durbin

I Stuart Linn

I Jonathan Pritchard

I Berkeley Center for Theoretical and Evolutionary Genomics

I National Institutes of Health

I National Science Foundation


Documents

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