Human Origins and Ancient Human DNA Cooper, Alan; Rambaut, Andrew; Macaulay, Vincent ...
Science (American Association for the Advancement of Science),
06/2001, Letnik:
292, Številka:
5522
Journal Article
The
CCR5-Δ
32 deletion obliterates the
CCR5 chemokine and the human immunodeficiency virus (HIV)–1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A ...genotype survey of 4,166 individuals revealed a cline of
CCR5-Δ
32 allele frequencies of 0%–14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between
CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the
CCR5-Δ
32–containing ancestral haplotype to be ∼700 years ago, with an estimated range of 275–1,875 years. The geographic cline of
CCR5-Δ
32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g., an epidemic of a pathogen that, like HIV-1, utilizes
CCR5), driving its frequency upward in ancestral Caucasian populations.
Abstract
Correction to Lindsay H, Yap VB, Ying H, Huttley GA: Pitfalls of the most commonly used models of context dependent substitution. Biology Direct 2008, 3:52
Rates of mutation and substitution in mammals are generally greater in the germ lines of males. This is usually explained as resulting from the larger number of germ cell divisions during ...spermatogenesis compared with oogenesis, with the assumption made that mutations occur primarily during DNA replication. However, the rate of cell division is not the only difference between male and female germ lines, and mechanisms are known that can give rise to mutations independently of DNA replication. We investigate the possibility that there are other causes of male-biased mutation. First, we show that patterns of variation at approximately 5,200 short tandem repeat (STR) loci indicate a higher mutation rate in males. We estimate a ratio of male-to-female mutation rates of approximately 1.9. This is significantly greater than 1 and supports a greater rate of mutation in males, affecting the evolution of these loci. Second, we show that there are chromosome-specific patterns of nucleotide and dinucleotide composition in mammals that have been shaped by mutation at CpG dinucleotides. Comparable patterns occur in birds. In mammals, male germ lines are more methylated than female germ lines, and these patterns indicate that differential methylation has played a role in male-biased vertebrate evolution. However, estimates of male mutation bias obtained from both classes of mutation are substantially lower than estimates of cell division bias from anatomical data. This discrepancy, along with published data indicating slipped-strand mispairing arising at STR loci in nonreplicating DNA, suggests that a substantial percentage of mutation may occur in nonreplicating DNA.
Continuous-time Markov processes are often used to model the complex natural phenomenon of sequence evolution. To make the process of sequence evolution tractable, simplifying assumptions are often ...made about the sequence properties and the underlying process. The validity of one such assumption, time-homogeneity, has never been explored. Violations of this assumption can be found by identifying non-embeddability. A process is non-embeddable if it can not be embedded in a continuous time-homogeneous Markov process. In this study, non-embeddability was demonstrated to exist when modelling sequence evolution with Markov models. Evidence of non-embeddability was found primarily at the third codon position, possibly resulting from changes in mutation rate over time. Outgroup edges and those with a deeper time depth were found to have an increased probability of the underlying process being non-embeddable. Overall, low levels of non-embeddability were detected when examining individual edges of triads across a diverse set of alignments. Subsequent phylogenetic reconstruction analyses demonstrated that non-embeddability could impact on the correct prediction of phylogenies, but at extremely low levels. Despite the existence of non-embeddability, there is minimal evidence of violations of the local time homogeneity assumption and consequently the impact is likely to be minor.
We report work to quantify the impact on the probability of human genome polymorphism both of recombination and of sequence context at different scales. We use population-based analyses of data on ...human genetic variants obtained from the public Ensembl database. For recombination, we calculate the variance due to recombination and the probability that a recombination event causes a mutation. We employ novel statistical procedures to take account of the spatial auto-correlation of recombination and mutation rates along the genome. Our results support the view that genomic diversity in recombination hotspots arises largely from a direct effect of recombination on mutation rather than predominantly from the effect of selective sweeps. We also use the statistic of variance due to context to compare the effect on the probability of polymorphism of contexts of various sizes. We find that when the 12 point mutations are considered separately, variance due to context increases significantly as we move from 3-mer to 5-mer and from 5-mer to 7-mer contexts. However, when all mutations are considered in aggregate, these differences are outweighed by the effect of interaction between the central base and its immediate neighbors. This interaction is itself dominated by the transition mutations, including, but not limited to, the CpG effect. We also demonstrate strand-asymmetry of contextual influence in intronic regions, which is hypothesized to be a result of transcription coupled DNA repair. We consider the extent to which the measures we have used can be used to meaningfully compare the relative magnitudes of the impact of recombination and context on mutation.
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