Evolution of Germline Mutation Spectrum in Humans

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Reconstructs whole-genome genealogies from 1000 Genomes (an ARG reconstruction placing ~10 million mutations on dated branches) and compares mutation-type ratios across equal-age bins while controlling for selection and biased gene conversion. Detects three clear shifts: a European-specific TCC→TTC ~20% enrichment that is temporal and no longer active, a still-ongoing divergence driven by elevated T→A rates, and very ancient T→C/T→G differences that predate Out-of-Africa. Shows parental-age changes cannot explain these patterns and points to genetic modifiers (mismatch-repair candidates) or environment.

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" chapters (18)

1. 0:00Intro
2. 0:42Lab focus: Human Evolutionary Genetics
3. 1:20Germline mutations are the ultimate source of genetic variation
4. 2:47The textbook view of mutation rate
5. 4:02Whole-genome sequencing of parent-offspring trio enables direct survey of germine mutations in one generation
6. 5:55Stable male-bias with age suggests underappreciated role of non-replicative sources to mutagenesis In humana
7. 7:30Whole genome sequencing of parent-affspring trio enables direct survey of germine mutations in one generation
8. 8:39Surprise 2: The unstable molecular clock: Large variation in substitution rates and spectrum across primates
9. 9:49The mutation spectrum of polymorphisms differ across human populations
10. 10:57The spectrum of polymorphisms is shaped by multiple evolutionary forces
11. 12:59How can we better characterize variation in mutation spectrum? We developed a new framework with following features: (1) Has a time dimension to allow reliable inter-population comparisons
12. 16:20Differences in pairwise ratios of polymorphisms across human populations
13. 17:47Northern European-specific acceleration in non-CpG CT mutations
14. 19:38Variation in CG/T A ratios among human populations
15. 20:54Variation in TC/T Gratis among human populations
16. 23:28Signal 3: Mutation signature related TC change in archaic ancestry regions in modern humans
17. 25:24Implications
18. 26:15Future Directions: Mutation rates in non-human species