Evidence for recent, population-specific evolution of the human mutation rate
Open accessAbstract
Significance: Most, but not all, human genetic variation is shared between populations, and whole-genome sequencing is now making it possible to catalogue population-private mutations that occur in only one ethnic group and are especially informative about recent human history. By contrasting frequencies of mutations private to Europe, Asia, and Africa, I have revealed a previously undetected difference between Europeans and other ethnic groups: Europeans experience higher rates of a specific mutation type that has known associations with UV light exposure. Although it is not clear whether the excess mutations are harmful or directly related to the UV sensitivity of light skin, this result demonstrates that the human mutation rate has evolved on a much faster timescale than previously believed.
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Written from the paper’s full text.
TL;DR
The paper reports that private European SNPs in the 1000 Genomes data are enriched for the C→T transition 5′-TCC-3′→5′-TTC-3′, suggesting a recent population-specific increase in this mutation type after Europeans diverged from Asians. The author argues this implies the human mutation rate has not remained stable over the last tens of thousands of years, though the mechanism and causality remain unresolved.
Key findings
- In the 1000 Genomes phase I data, private European SNPs (462,876) had a higher percentage of C→T transitions (41.01%) than private Asian SNPs (38.99%) and private African SNPs (38.29%).
- The transition 5′-TCC-3′→5′-TTC-3′ plus its reverse-strand complement had frequency 3.32% in private European SNPs, compared with 1.98% in private African SNPs and 2.04% in private Asian SNPs; the abstract reports a 50% frequency increase during the 40,000–80,000 y since Europeans began diverging from Asians, while ARGweaver-based estimates place acceleration between 25,000 and 60,000 y ago.
- TCC→T was the only mutation type with a significant strand-bias difference between populations at P < 0.01: private European TCC→T SNPs showed no discernible strand bias, whereas private Asian and African TCC→T SNPs showed the typical A/C→G/T strand bias.
- European private genic SNPs had higher f(TCC) than intergenic SNPs, while Asian and African private genic sets had lower TCC→T frequencies, suggesting less effective transcription-coupled repair of TCC→T in Europeans; TCC→T is also described as the most common somatic mutation in melanoma and the mutation most frequently induced in vitro by UV.
Methods
- Analyzed 1000 Genomes phase I data from 1,092 human genomes, constructing population-private SNP sets for Europe (PE), Asia (PAs), and Africa (PAf), plus shared European-Asian SNPs (PAsE); singletons and variants with imputation quality RSQ < 0.95 were excluded, and ancestral states were inferred using the UCSC chimp PanTro4 alignment to hg19.
- Used Pearson’s χ² tests to compare mutation-type frequencies between SNP sets, nonparametric bootstrapping in bins of 1,000 consecutive SNPs within chromosomes, and χ² tests for transcription-strand bias using UCSC gene annotations.
- Compared results with Complete Genomics high-coverage genomes and with de novo mutation calls from 82 Icelandic trios.
Limitations
- Stated: The paper says it cannot pinpoint why the TCC→T rate increased and whether UV played a causal role; it cautions that the asymmetry could be confounded by bioinformatic biases, especially because 1000 Genomes phase I is heavily imputed and contains more European than Asian genomes, which could inflate rare European variant ascertainment.
- Stated: The author notes that current data cannot tell whether skin lightening predated TCC→T acceleration, and that the mechanism linking UV to germ-line mutations is unclear.
- Evident from the text: The inference relies on population-private SNPs and ancestral-state calls rather than direct de novo mutation measurement in non-Europeans, and the UV/melanoma connection is correlative rather than causally tested.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
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- Findingown data
The TCC to T frequency difference between Europeans and other populations is present across the genome, on every chromosome except chromosome Y.
“The TCC → T frequency difference holds genome-wide, evident on every chromosome except for chromosome Y, which has too little population-private variation to yield accurate measurements of context-dependent SNP frequencies (Fig. 1E).”
Quote in the paperSubstantial claim - Findingcitation
The TCC to T excess in Europe is reproduced in high-coverage Complete Genomics genomes.
“To rule out the possibility that TCC → T excess in Europe is a bioinformatic artifact specific to the 1000 Genomes data, I reproduced Fig. 1 A and B in a set of human genomes sequenced at high coverage using Complete Genomics technology (SI Appendix, section 3) (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
- Findingown data§ Evidence for recent, population-specific evolution of the human mutation rate
In the 1000 Genomes data, SNPs private to Europe are enriched for the TCC to TTC transition compared with SNPs private to Africa and Asia.
“A comparison of SNPs private to Africa, Asia, and Europe in the 1000 Genomes data reveals that private European variation is enriched for the transition 5′-TCC-3′ → 5′-TTC-3′.”
Quote in the paperSubstantial claim - Findingown data
Among mutation types, TCC to T and a few other C to T transitions show the clearest evidence of accelerated rate in Europeans.
“TCC → T and a few other C → T transitions exhibit the clearest evidence of European rate acceleration, but other mutation types might have experienced smaller rate changes within Europeans or other human populations.”
Quote in the paperNot a substantial claim - Findingreasoning
Among private European SNPs, f(TCC) is higher in genic than intergenic regions.
“As predicted by this logic, f ðTCCÞ is higher among private genic European SNPs than among private intergenic European SNPs (Fig. 3F).”
Quote in the paperSubstantial claim- The authors state this as an assumption: The TCC to T mutation rate is the same in genic and intergenic regions in Europeans because transcription-coupled repair is ineffective at preventing TCC to T mutations in Europeans.
- Findingown data
Europeans experience higher rates of a specific mutation type that has known associations with UV light exposure.
“By contrasting frequencies of mutations private to Europe, Asia, and Africa, I have revealed a previously undetected difference between Europeans and other ethnic groups: Europeans experience higher rates of a specific mutation type that has known associations with UV light exposure.”
Quote in the paperSubstantial claim - Findingown data
Genomic regions differing in GC content and/or sequencing depth show little consistency in which mutation types have the most frequency differentiation between Africa and Asia.
“In contrast, genomic regions that differ in GC content and/or sequencing depth show little consistency as to which mutation types show the most frequency differentiation between Africa and Asia.”
Quote in the paperSubstantial claim - Findingown data
In private Asian and African SNP sets, genic sets have lower TCC to T frequencies than intergenic sets.
“In contrast, when PAs and PAf are partitioned into genic and intergenic SNPs, the genic SNP sets have lower TCC → T frequencies, suggesting that TCR of this mutation type is relatively efficient in non-Europeans.”
Quote in the paperSubstantial claim - Findingown data
Within Europe, there is a slight north-to-south f(TCC) gradient, with median f(TCC) lowest in Finns and highest in Spanish and Italians.
“Within Europe, Fig. 2 shows a slight f ðTCCÞ gradient running from north to south; the median f ðTCCÞ is lowest in the Finns and highest in the Spanish and Italians.”
Quote in the paperNot a substantial claim - Findingown data
Three other C to T transitions, TCT to TTT, ACC to ATC, and CCC to CTC, are more abundant in Europe than in Africa across a broad range of GC contents and sequencing depths.
“Three other C → T transitions (TCT → TTT, ACC → ATC, and CCC → CTC) are also more abundant in Europe than in Africa across a broad range of GC contents and sequencing depths.”
Quote in the paperSubstantial claim - Findingnone given
TTA to TAA mutations seem to be less abundant in Europe than in Africa.
“C → T transitions may not be the only mutations that experienced recent rate change; for example, TTA → TAA mutations seem to be less abundant in Europe than in Africa.”
Quote in the paperNot a substantial claim - Findingown data
TCC to T is the only mutation type with a significant strand bias difference between populations at P < 0.01.
“TCC → T is the only mutation type that exhibits a significant strand bias difference between populations at the level P < 0:01.”
Quote in the paperSubstantial claim - Findingown data
All five European subpopulations in the 1000 Genomes phase I dataset have elevated TCC to T frequencies.
“All of these populations have elevated TCC → T frequencies, suggesting that the European mutation rate changed before subpopulations diversified across the continent.”
Quote in the paperSubstantial claim - Findingown data
Several other C to T transitions are also moderately more abundant in private European SNPs than in private African SNPs, in most cases flanked by either a 5′ T or a 3′ C.
“Several other C → T transitions are also moderately more abundant in PE than PAf, in most cases flanked by either a 5′ T or a 3′ C.”
Quote in the paperSubstantial claim - Findingown data
The strongest candidate for mutation rate change is the transition TCC to T.
“As shown in Fig. 1A, the strongest candidate for mutation rate change is the transition 5′-TCC-3′ → 5′-TTC-3′ (hereafter abbreviated as TCC → T).”
Quote in the paperSubstantial claim - Findingown data
Admixed American populations display broader ranges of f(TCC) with extremes overlapping both European and non-European distributions.
“In contrast, the four admixed populations ASW (African Americans), MXL (Mexicans), PUR (Puerto Ricans), and CLM (Colombians) display broader ranges of f ðTCCÞ with extremes overlapping both the European and non-European distributions.”
Quote in the paperSubstantial claim - Findingown data
In the 1000 Genomes data, TCC to T frequency differentiation is greatest for private alleles with frequency less than 0.02.
“In the 1000 Genomes data, TCC → T frequency differentiation is greatest for private alleles of frequency less than 0.02 (SI Ap- pendix, Fig. S6B).”
Quote in the paperSubstantial claim - Findingown data§ Evidence for recent, population-specific evolution of the human mutation rate
The rate of TCC to T mutation recently increased in the European population, rising in frequency by 50% during the 40,000 to 80,000 years since Europeans began diverging from Asians.
“Here, I present evidence that the rate of a particular mutation type has recently increased in the European population, rising in frequency by 50% during the 40,000-80,000 y since Europeans began diverging from Asians.”
Quote in the paperSubstantial claim - Findingown data
Including singleton variants creates spurious between-population differences that are not reproducible with nonsingleton SNPs.
“When singletons are included they create spurious between-population differences that are not reproducible with nonsingleton SNPs (SI Appendix, section 8).”
Quote in the paperSubstantial claim - Findingown data
Private European TCC to T SNPs exhibit no discernible strand bias, with the C to T change affecting the sense strand about 50% of the time.
“In contrast, private European TCC → T SNPs exhibit no discernible strand bias; the C → T change affects the sense strand about 50% of the time (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
The distribution of f(TCC) values in Europe does not overlap with the distributions from Asia and Africa.
“For each 1000 Genomes population P, Fig. 2 shows the distribution of f h ðTCCÞ across all haplotypes h sampled from P, and it can be seen that the distribution of f ðTCCÞ values found in Europe does not overlap with the distributions from Asia and Africa.”
Quote in the paperSubstantial claim - Findingown data
The percentage of C to T transitions is higher in private European SNPs (41.01%) than in private Asian SNPs (38.99%) or private African SNPs (38.29%).
“One notable feature of PE is the percentage of SNPs that are C → T transitions, which is higher (41.01%) than the corresponding percentages in PAs (38.99%) and PAf (38.29%).”
Quote in the paperSubstantial claim - Findingown data
TCC to TTC frequency seems to correlate negatively with recent Asian coancestry.
“In this way, TCC → TTC frequency seems to correlate negatively with recent Asian coancestry (SI Appendix, section 2).”
Quote in the paperNot a substantial claim - Findingown data
African American and Latin American populations, which are admixed, have intermediate frequencies of TCC to T mutations.
“The slightly admixed African Americans and more strongly admixed Latin American populations have intermediate f ðTCCÞ values reflecting partial European ancestry.”
Quote in the paperSubstantial claim - Findingown data
The mutation 5'-TCC-3' to 5'-TTC-3' is overrepresented within Europe.
“Overrepresentation of 5′-TCC-3′ → 5′-TTC-3′ within Europe.”
Quote in the paperSubstantial claim - Findingown data
The frequency of TCC to T mutations is clearly lower in African and Asian genomes than in European genomes.
“There is a clear division between the low f ðTCCÞ values of African and Asian genomes and the high f ðTCCÞ values of European genomes.”
Quote in the paperSubstantial claim - Interpretationreasoning
The most parsimonious explanation for the European TCC to T excess is that Europeans experienced a genetic change that increased the rate of TCC to T mutations.
“The most parsimonious explanation is that Europeans experienced a genetic change increasing the rate of TCC → T mutations.”
Quote in the paperSubstantial claim - Interpretationreasoning
The higher f(TCC) values in some African Americans are presumably due to greater European ancestry.
“The African American f ðTCCÞ values are only slightly higher on average than the nonadmixed African values, but a few African American individuals have much higher f ðTCCÞ values in the middle of the admixed American range, presumably because they have more European ancestry than the other African Americans who were sampled.”
Quote in the paperNot a substantial claim - Interpretationown data
The European population underwent a recent increase in its mutation rate.
“Although the data presented here do not reveal a clear mechanism, they leave little doubt that the European population experienced a recent mutation rate increase.”
Quote in the paperSubstantial claim - Interpretationreasoning
The transcription-coupled repair differential is not likely to be the sole cause of the observed TCC to T rate acceleration because the acceleration is evident in both genic and intergenic regions.
“However, it is not likely to be the sole cause of the observed TCC → T rate acceleration because this acceleration is evident in both genic and intergenic regions.”
Quote in the paperSubstantial claim - Interpretationreasoning
The human mutation rate has evolved on a much faster timescale than previously believed.
“Although it is not clear whether the excess mutations are harmful or directly related to the UV sensitivity of light skin, this result demonstrates that the human mutation rate has evolved on a much faster timescale than previously believed.”
Quote in the paperSubstantial claim - Interpretationown data
The European mutation rate change occurred before European subpopulations diversified across the continent.
“All of these populations have elevated TCC → T frequencies, suggesting that the European mutation rate changed before subpopulations diversified across the continent.”
Quote in the paperSubstantial claim - Premisecitation
An attempt to date the origin of the SLC24A5 allele yielded a 95% confidence interval of 6,000 to 38,000 years ago, overlapping with the time interval when TCC to T rate seems to have accelerated.
“An attempt to date the origin of this allele yielded a 95% confidence interval of 6,000-38,000 y ago (26), which overlaps with the time interval when the TCC → T rate seems to have accelerated.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] source
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- Interpretationreasoning
The transcription-coupled repair differential alone could modestly elevate the European TCC to T mutation rate.
“This TCR differential alone could modestly elevate the European TCC → T mutation rate.”
Quote in the paperNot a substantial claim - Premisecitation
A 7,000-year-old Early European farmer was homozygous for the skin-lightening SLC24A5 allele.
“A 7,000-y-old Early European farmer was found to be homozygous for the skinlightening SLC24A5 allele (25), suggesting that light skin was relatively prevalent by 7,000 y ago and could have originated much earlier.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] source
Not checked in the free run.
- Interpretationcitation
There is reason to suspect that mutation rates might have changed owing to recent regional adaptations affecting DNA repair.
“However, there is some reason to suspect that mutation rates might have changed owing to recent regional adaptations affecting DNA repair.”
Quote in the paperSubstantial claim - Interpretationown data
By rank ordering, Icelandic mutations resemble private European SNPs more closely than private Asian SNPs, as expected for European trios.
“By this measure, the Icelandic mutations resemble PE more closely than PAs, as expected for European trios.”
Quote in the paperNot a substantial claim - Interpretationown data
Transcription-coupled repair of TCC to T is relatively efficient in non-Europeans.
“In contrast, when PAs and PAf are partitioned into genic and intergenic SNPs, the genic SNP sets have lower TCC → T frequencies, suggesting that TCR of this mutation type is relatively efficient in non-Europeans.”
Quote in the paperSubstantial claim - Premisecitation
Prüfer et al. used a similar technique to quantify divergence between archaic and modern genomes and found that branch length differences between sequencing batches often exceeded branch length differences between populations.
“Prüfer et al. (22) used a similar technique to quantify divergence between archaic and modern genomes and found that branch length differences between sequencing batches often exceeded branch length differences between populations.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] source
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- Premiseown data
CCC to CTC and TCT to TTT are also prominent in the melanoma spectrum.
“The mutation types CCC → CTC and TCT → TTT, two other candidates for rate acceleration in Europe, are also prominent in the spectrum of melanoma (SI Appendix, section 11).”
Quote in the paperNot a substantial claim - Premisecitation
High CpG mutation rates make these sites especially susceptible to ancestral state miscalls.
“This is not surprising given that high CpG mutation rates makes these sites especially susceptible to ancestral state miscalls (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
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- Premisecitation
The older assumption that the human lineage's mutation rate changed little since the human-chimpanzee common ancestor is losing credibility because direct mutation rate estimates conflict with molecular-clock-based estimates.
“It was once assumed that the human lineage's mutation rate had changed little since we shared a common ancestor with chimpanzees, but this assumption is losing credibility owing to the conflict between direct mutation rate estimates and molecular-clock-based estimates (8,9).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Even a small European mutation rate increase supports the view that molecular clock assumptions fail over a shorter timescale than is usually supposed in population genetic analysis.
“Even if the overall European mutation rate increase was small, it adds to a growing body of evidence that molecular clock assumptions break down on a faster timescale than generally assumed during population genetic analysis.”
Quote in the paperSubstantial claim - Interpretationown data
Singletons are error-prone even in high-coverage genomes.
“This is true of both the low-coverage 1000 Genomes dataset and the smaller, higher-coverage Complete Genomics dataset, suggesting that singletons are error-prone even in highcoverage genomes.”
Quote in the paperSubstantial claim - Interpretationown data
The intermediate TCC to T frequencies in admixed American populations are explained by their partial European ancestry.
“The slightly admixed African Americans and more strongly admixed Latin American populations have intermediate f ðTCCÞ values reflecting partial European ancestry.”
Quote in the paperSubstantial claim
- May combine two claims. 25
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 12
May combine two claims.
Findingown dataThe combined frequency of TCC to T and its reverse complement GGA to GAA is 3.32% among private European SNPs, 1.98% among private African SNPs, and 2.04% among private Asian SNPs.
“Combined with its reverse strand complement 5′-GGA-3′ → 5′-GAA-3′, TCC → T has frequency 3.32% in PE compared with 1.98% in PAf and 2.04% in PAs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMany mutation types occur at slightly higher rates in Europe than in Asia, with C to T transitions, especially TCC to T, showing the strongest signal of rate differentiation.
“The results suggest that many mutation types occur at slightly higher rates in Europe compared with Asia, with C → T transitions, particularly TCC → T, showing the strongest signal of rate differentiation.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationBased on ARGweaver allele age estimates, TCC to T rate acceleration seems to have occurred between 25,000 and 60,000 years ago, not long after Europeans diverged from Asians.
“Based on these estimates, TCC → T rate acceleration seems to have occurred between 25,000 and 60,000 y ago, not long after Europeans diverged from Asians (SI Appendix, section 4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] source
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May combine two claims.
FindingreasoningAfrican American f(TCC) values are only slightly higher on average than nonadmixed African values, but a few African American individuals have much higher values in the middle of the admixed American range.
“The African American f ðTCCÞ values are only slightly higher on average than the nonadmixed African values, but a few African American individuals have much higher f ðTCCÞ values in the middle of the admixed American range, presumably because they have more European ancestry than the other African Americans who were sampled.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn private European SNPs, TCC to TTC and its complement GGA to GAA rank 16th and 17th most common SNP types, whereas in private Asian SNPs they rank 27th and 32nd.
“In PE, TCC → TTC and its complement GGA → GAA are the 16th and 17th most common SNP types, respectively, whereas they are only ranked 27th and 32nd in PAs.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationPrivate Asian and African TCC to T SNPs exhibit the strand bias typical of A/C to G/T mutations, with the C to T change usually affecting the antisense strand and the G to A change usually affecting the sense strand.
“Private Asian and African TCC → T SNPs were found to exhibit the strand bias that is typical of A/C → G/T mutations (28), with the C → T change usually affecting the antisense strand and the G → A change usually affecting the sense strand.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Findingown dataAfter excluding singletons and SNPs with imputation quality lower than RSQ = 0.95, there remain 462,876 private European SNPs, 265,988 private Asian SNPs, and 3,357,498 private African SNPs.
“there remain 462,876 private European SNPs (PE) that are variable in Europe but fixed ancestral in all nonadmixed Asian and African populations, as well as 265,988 private Asian SNPs (PAs) that are variable in Asia but fixed ancestral in Africa and Europe.”
- Also stated in: § Significance · plain
“I compared PE and PAs to the set of 3,357,498 private African SNPs (PAf) that are variable in the Yorubans (YRI) and/or Luhya (LWK) but fixed ancestral in Europe and Asia.”
Quote in the paperSubstantial claim- Also stated in: § Significance · plain
May combine two claims.
Findingown dataSeveral CpG transitions including ACG to ATG seem to have higher frequencies in Asia than in Africa, but these differences disappear when the spectrum is folded.
“Several CpG transitions including ACG → ATG seem to have higher frequencies in Asia than in Africa, but these differences disappear when the spectrum is folded to, for instance, identify ACG → ATG with the inverse mutation ATG → ACG (SI Appendix, section 5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt the 0.01 significance level, TCC to T is the only mutation type whose transcriptional strand bias differs significantly between Europe and Africa, and no mutation type differs significantly in strand bias between Asia and Africa.
“At the P = 0:01 significance level (gray dashed line), only TCC → T has a significant strand bias difference between Europe and Africa, whereas no mutation type significantly differs in strand bias between Asia and Africa.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Evidence for recent, population-specific evolution of the human mutation rateDNA replication fidelity has not remained stable since the origin of modern humans and might have changed numerous times during recent human evolutionary history.
“Regardless of its causality, this change indicates that DNA replication fidelity has not remained stable even since the origin of modern humans and might have changed numerous times during our recent evolutionary history.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationLight skin was relatively prevalent by 7,000 years ago and could have originated much earlier.
“A 7,000-y-old Early European farmer was found to be homozygous for the skinlightening SLC24A5 allele (25), suggesting that light skin was relatively prevalent by 7,000 y ago and could have originated much earlier.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThis ascertainment difference could produce a false overall excess of European-derived alleles but seems unlikely to elevate the discovery rate of TCC to T in Europe relative to other mutation types.
“This could produce a false overall excess of European-derived alleles but seems unlikely to elevate the discovery rate of TCC → T in Europe relative to other mutation types.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExcess C to T transitions are characteristic of several mutagenic processes including UV damage and cytosine deamination.
“Excess C → T transitions are characteristic of several different mutagenic processes including UV damage and cytosine deamination (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] source
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PremisecitationMelanoma incidence in admixed Hispanics is strongly correlated with European ancestry.
“Melanoma incidence in admixed Hispanics is strongly correlated with European ancestry (33)(34)(35).”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
Premisenone givenUltraviolet radiation causes TCC to T mutations.
“Despite the strong evidence that UV causes TCC → T mutations, the question remains how UV could affect germ-line cells that are generally shielded from solar radiation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMelanoma is associated with UV light exposure and European ancestry, occurring at very low rates in Africans, African Americans, and light-skinned Asians.
“Incidentally, melanoma is not only associated with UV light exposure but also with European ancestry, occurring at very low rates in Africans, African Americans, and even light-skinned Asians (32)(33)(34).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataBeyond a possible gradual decline in germ-line mitoses per year as generation times lengthened, the results of this study indicate that a change in the mutation rate per mitosis may also have operated.
“Although this conflict might have arisen from a gradual decrease in the rate of germ-line mitoses per year as our ancestors evolved longer generation times (12,13), the results of this paper indicate that another force may have come into play: change in the mutation rate per mitosis.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12]
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- cites [13] source
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PremisecitationIn Icelandic trio de novo mutations, TCC to TTC and GGA to GAA rank 20th and 18th.
“In the Icelandic trios, TCC → TTC and GGA → GAA are ranked 20th and 18th.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisereasoningBecause the 1000 Genomes phase I dataset is heavily imputed and contains more European genomes than Asian genomes, rare European variants might be ascertained more completely than rare Asian variants.
“In addition, because the 1000 Genomes phase I dataset is heavily imputed and contains more European genomes than Asian genomes, rare European variants might be ascertained more completely than rare Asian variants.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationUV cross-links TC into a base dimer lesion, and repair efficacy is poorer at TCC than at other motifs where UV lesions can form.
“The association of TCC → T mutations with UV exposure is not well understood, but two factors seem to be in play: (i) the propensity of UV to cross-link the TC into a base dimer lesion and (ii) poorer repair efficacy at TCC than at other motifs where UV lesions can form (36,37).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premiseown dataMost human trios sequenced are European in origin, so few measurements of de novo mutation patterns exist on diverse genetic backgrounds.
“Most human trios that have been sequenced are European in origin (SI Appendix, section 9), meaning that there exist few measurements of de novo mutation patterns on diverse genetic backgrounds.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMelanoma somatic mutations consist almost entirely of C to T transitions, 28% of which are TCC to T mutations.
“Melanoma somatic mutations consist almost entirely of C → T transitions, 28% of which are TCC → T mutations (19,31).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone given§ Evidence for recent, population-specific evolution of the human mutation rateTCC to T is known to be the most common somatic mutation in melanoma skin cancers and the mutation most frequently induced in vitro by UV.
“Although it is not clear whether UV played a causal role in changing the European mutational spectrum, 5′-TCC-3′ → 5′-TTC-3′ is known to be the most common somatic mutation present in melanoma skin cancers, as well as the mutation most frequently induced in vitro by UV.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTCC to T dominated the mutational spectra of single genes isolated from UV-irradiated cell cultures.
“In the mid-1990s, Drobetsky et al. (29) and Marionnet et al. (30) observed that TCC → T dominated the mutational spectra of single genes isolated from UV-irradiated cell cultures.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn the California Cancer Registry, annual age-adjusted melanoma incidence per 100,000 people was 0.8 to 0.9 for Asians, 0.7 to 1.0 for African Americans, and 11.3 to 17.2 for Caucasians.
“A study of the California Cancer Registry found that the annual age-adjusted incidence of melanoma cases per 100,000 people was 0.8-0.9 for Asians, 0.7-1.0 for African Americans, and 11.3-17.2for Caucasians (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] source
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PremisecitationSNPs affecting gene expression in DNA damage response pathways show evidence of recent diversifying selection, with geographic frequency gradients correlated with environmental UV exposure.
“SNPs that affect gene expression in DNA damage response pathways show evidence of recent diversifying selection, exhibiting geographic frequency gradients that seem to be correlated with environmental UV exposure (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] source
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May combine two claims.
PremisecitationTCC motifs are not hotspots for UV lesion formation but are disproportionately likely to have lesions develop into mutations rather than undergo error-free repair.
“Drobetsky et al. (29) compared the incidence of UV lesions to the incidence of mutations in irradiated cells and found that TCC motifs were not hotspots for lesion formation but instead were disproportionately likely to have lesions develop into mutations rather than undergoing error-free repair.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] source
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Study design and conductnone givenThe definitions used for the private SNP sets were designed to select mutations that stayed confined to one continent for most of their history, apart from possible recent spread to the Americas.
“These definitions are meant to select for mutations that have been confined to a single continent for most of their history except for possible recent transmission to the Americas.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningSingletons were removed to limit the effect of sequencing error, and variants with imputation quality below RSQ = 0.95 were removed to limit wrongly labelling shared SNPs as population-private.
“Singletons are excluded to minimize the impact of possible sequencing error, and variants with imputation quality lower than RSQ = 0:95 are excluded to minimize erroneous designation of shared SNPs as population-private.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationCpG transitions accumulate in a more clocklike manner than other mutations.
“Given such a general challenge to the molecular clock assumption, it may be wise to infer demographic history from mutations such as CpG transitions that accumulate in a more clocklike way than other mutations (8,20).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.
InterpretationreasoningIf the mutagenic spectrum could change within the last 60,000 years of human history, it may have changed many times during great ape evolution and before it.
“If the mutagenic spectrum was able to change during the last 60,000 y of human history, it might have changed numerous times during great ape evolution and beforehand.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The TCC to T mutation rate is the same in genic and intergenic regions in Europeans because transcription-coupled repair is ineffective at preventing TCC to T mutations in Europeans.
“If we assume that the TCC → T mutation rate is the same in genic and intergenic regions because TCR is ineffective at preventing TCC → T mutations in Europeans, we should expect the frequency f ðTCCÞ to be slightly higher among private genic SNPs than among private intergenic SNPs.”
The paper relies on this without support.
The observed European excess of TCC to T mutations is not explained by demographic events such as a population bottleneck.
“This asymmetry cannot be explained by a demographic event such as a population bottleneck; however, it should be interpreted with caution because many bioinformatic biases have the potential to confound this test.”
The paper relies on this without support.
Previous studies have presented no evidence of mutation rate evolution on a timescale as recent as the human migration out of Africa.
“To my knowledge, previous studies have presented no evidence of mutation rate evolution on a timescale as recent as the human migration out of Africa.”
The paper relies on this without support.
The private SNPs used in the analysis are enriched for young mutations that arose after humans left Africa and began adapting to temperate latitudes.
“These SNPs should be enriched for young mutations that arose after humans had already left Africa and begun adapting to temperate latitudes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Both Denisovan and Neanderthal aSNPs, especially those within protein coding and conserved non-coding elements, are mostly deleterious and negatively selected in modern humans.
“Evidence indicates that both Denisovan and Neanderthal aSNPs, especially those within protein coding and conserved non-coding elements, are mostly deleterious and negatively selected in modern humans [14, 61].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [61]
The Materials and Methods and Significance passages describe population-private SNPs and differences in mutation rates, not the effects of Denisovan or Neanderthal aSNPs in modern humans. Searches for archaic SNPs, deleterious effects, and selection in coding or conserved non-coding elements found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citationThe population genetics of ploidy change in unicellular fungi
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Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme
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Mutation bias and the predictability of evolution
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Statistical Methods for Identifying Sequence Motifs Affecting Point Mutations
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Legacy Data Confound Genomics Studies
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Evolution of the Mutation Spectrum Across a Mammalian Phylogeny
Beichman, A. C., Robinson, J. A., Lin, M., Moreno‐Estrada, A., Nigenda‐Morales, S. F., & Harris, K. (2023) · Molecular Biology and Evolution · doi:10.1093/molbev/msad213 · Cited by 26 · see citing works
Self-citationThe evolution of the human genome
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Inferring evolutionary dynamics of mutation rates through the lens of mutation spectrum variation
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Self-citationSignificant Strain Variation in the Mutation Spectra of Inbred Laboratory Mice
Dumont, B. L. (2019) · Molecular biology and evolution · doi:10.1093/molbev/msz026 · Cited by 28 · see citing works
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Signals of Variation in Human Mutation Rate at Multiple Levels of Sequence Context
Aikens, R. C., Johnson, K. E., & Voight, B. F. (2019) · Molecular Biology and Evolution · doi:10.1093/molbev/msz023 · Cited by 23 · see citing works
The Evolutionary Interplay of Somatic and Germline Mutation Rates
Beichman, A. C., Zhu, L., & Harris, K. (2024) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-102523-104225 · Cited by 23 · see citing works
Self-citationLimited role of generation time changes in driving the evolution of the mutation spectrum in humans
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Mutational bias and the protein code shape the evolution of splicing enhancers
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Inference of Candidate Germline Mutator Loci in Humans from Genome-Wide Haplotype Data
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Somatic maintenance impacts the evolution of mutation rate
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Comparison of Compression-Based Measures with Application to the Evolution of Primate Genomes
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Estimation of demography and mutation rates from one million haploid genomes
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Modern human DNA analyses with special reference to the inner dual-structure model of Yaponesian
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Distinct landscapes of deleterious variants in DNA damage repair system in ethnic human populations
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Multiple Sources of Uncertainty Confound Inference of Historical Human Generation Times
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Self-citation
- Authors
- Harris, K.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Harris, Kelley
- ORCID
- Harris, Kelley
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-03-02
- Volume
- 112
- Issue
- 11
- Pages
- 3439-3444
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4371947
- OpenAlex
- W2115741580
- Semantic Scholar
- 43a60e7b197d8f860145743b4fc95a6b8ec0cbbe
- Cited by
- 165
- References
- 47
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 10 · 2023: 15 · 2022: 19 · 2021: 20 · 2020: 19 · 2019: 14 · 2018: 9 · 2017: 11 · 2016: 21 · 2015: 8
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1000078615)
- HHS | National Institutes of Health (IR01GM109454-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- mutation spectrum, UV mutagenesis, DNA replication fidelity, local adaptation, European populations, melanoma, DNA damage response, human dispersal out of Africa, 1000 Genomes Project
- MeSH terms
- Europe, Biological Evolution, Genetics, Population, Humans, Mutation, Transcription, Genetic, Genetic Variation, Computational Biology, Mutation Rate
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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