The Human Genome and Human Evolution Y Chromosome

1. The Human Genome and Human EvolutionY Chromosome Dr Derakhshandeh, PhD

2. Outline • Information from fossils and archaeology • Neutral (or assumed-to-be-neutral) genetic markers • Classical markers • Y chromosome • Genes under selection • Balancing selection: • Balancing selection can arise by the heterozygotes having a selective advantage, as in the case of sickle cell anemia • It can also arise in cases where rare alleles have a selective advantage • Positive selection

3. Why Y? • "Adam passed a copy of his Y chromosome to his sons • The Y chromosome is paternally inherited • the Y chromosome a father passes to his son is, in large measure, an unchanged copy of his own

5. But small changes (called polymorphisms) do occur • passed down from generation to generation

6. CHROMOSOME CHANGES • indels • insertions into or deletions of the DNA at particular locations on the chromosome • YAP • which stands for ”Y chromosome Alu Polymorphism” • Alu is a sequence of approximately 300 letters (base pairs) which has inserted itself into a particular region of the DNA

7. Snips • "single nucleotide polymorphisms“ • Stable indels and snips are relatively rare • so infrequent • they have occurred at any particular position in the genome only once in the course of human evolution • Snips and stable Alus have been termed "unique event polymorphisms" (UEPs)

8. microsatellites • short sequences of nucleotides (such as GATA) • repeated over and over again a variable number of times in tandem • The specific number of repeats in a particular variant (or allele) usually remains unchanged from generation to generation • but changes do sometimes occur and the number of repeats may increase or decrease

9. increases or decreases in the number of repeats take place in single steps • for instance from nine repeats to ten • whether decreases in number are as common as increases has not been established

10. Changes in microsatellite length occur much more frequently than new UEPs arise (Snips and stable Alus : "unique event polymorphisms) • while we can reasonably assume that a UEP has arisen only once • the number of repeat units in a microsatellite may have changed many times along a paternal lineage

11. The microsatellite data • can facilitate the estimation of population divergence times • which can then be compared (and contrasted) with estimated mutational ages of the polymorphic markers • the combination of these two kinds of data: • offers a powerful tool with which to assess patterns of migration, admixture, and ancestry

12. minisatellites • 10-60 base pairs long • the number of repeats often extends to several dozen • Changes during the copying process take place more frequently in minisatellites than in microsatellites

13. the evolutionary clock • the UEPs as the hour hand • the microsatellite polymorphisms as the minute hand • the minisatellites as a sweep second hand

14. a further benefit of using “Y chromosome” to study evolution • most of the Y chromosome does not exchange DNA with a partner • all the markers are joined one to another along its entire length • linkage of markers

15. The human Y chromosome • can also be used to draw evolutionary trees • the relationships of the Y chromosomes of other primates • The different polymorphic loci are distinguished from each other by their chain lengths • it can be measured using an automatic DNA sequencer

16. Gene scan output of microsatellite DNA analysis from a single individual The microsatellite peaks are sorted by size, the different colors representing different microsatellites. The small red peaks are size markers

17. new UEP arises in a certain man • As the new UEP is copied from generation to generation • The UEP does not change but, albeit not very often: • increasing • decreasing in length • The longer the time since the UEP arose • the greater will be the number of different UEP allele

18. Such a process: • differentiates one population from another • the more closely two populations • display common haplotype frequencies • the more closely related is their biological history likely to be

19. IN ANCIENT TIMES • only the analysis of DNA obtained from our contemporaries • suggested ways in which we might deduce past history from an interpretation of those data: • DNA can be extracted from ancient remains

20. Amelogenin gene • exists in two forms: • the one on the X chromosome being different in length from the one on Y • Small portions of: • cranial bones • and teeth • were crushed to powder and decalcified

21. The amelogenin gene • is a single copy gene • homologues of which are located on: • Xp22.1-Xp22.3 • and Yp 11.2

22. Yp 11.2

23. DNA was purified • copied by PCR using primers flanking the region • the size of the products was measured by agarose gel electrophoresis • Since Y chromosomes yield fragments 218 base pairs long • while X chromosome products contain 330 base pairs • they should be clearly distinguishable: • if the specimen yields the shorter gene, it must come from a Y chromosome fragment and thus from a male.

24. Disadvantages • DNA is often degraded • so that continuous fragments are no longer present • cannot be copied • substances may be present: • inhibit both purification and amplification

25. The first two human Y chromosome marker • studies appeared in 1985 (Casanova et al. 1985; Lucotte and Ngo 1985) • It was not until almost a decade later that Torroni and co-workers (1994a) published the first Y chromosome data on Native Americans • Numerous surveys of variation on the non-recombining portion of the Y chromosome (NRY)

26. Who are our closest living relatives? Chen FC & Li WH (2001) Am. J. Hum. Genet.68 444-456

27. selected 53 autosomal / Y Ch intergenic nonrepetitive DNA segments from the • human genome and sequenced them in a human, a chimpanzee, a gorilla, and an orangutan.

28. The average sequence • divergence was only 1.24% +/- 0.07% for the human-chimpanzee pair • 1.62% +/- 0.08% for the human-gorilla Pair • and 1.63% +/- 0.08% for the chimpanzee-gorilla pair

29. Taking the orangutan speciation date as 12 to 16 million years ago • an estimate of 4.6 to 6.2 million years for the Homo-Pan divergence • an estimate of 6.2 to 8.4 million years for the gorilla speciation date • gorilla lineage branched off 1.6 to 2.2 million years earlier than did the human-chimpanzee divergence 4.6 to 6.2 million 1.6 to 2.2 million 6.2 to 8.4 million 12 to 16 million

30. Phenotypic differences between humans and other apes *Carroll (2003) Nature422, 849-857

31. Chimpanzee-human divergence 6-8 million years Hominids or hominins Chimpanzees Humans

32. Origins of hominids • Sahelanthropus tchadensis • Chad (Central Africa) • Dated to 6 – 7 million years ago • Posture uncertain, but slightly later hominids were bipedal ‘Toumai’, Chad, 6-7 MYA Brunet et al. (2002) Nature418, 145-151

33. Hominid fossil summary Found only in Africa Found both in Africa and outside, or only outside Africa

34. Origins of the genus Homo • Homo erectus/ergaster ~1.9 million years ago in Africa • Use of stone tools • H. erectus in Java ~1.8 million years ago Nariokatome boy, Kenya, ~1.6 MYA

35. Additional migrations out of Africa • First known Europeans date to ~800 KYA • Ascribed to H. heidelbergensis

36. Origins of modern humans (1) • Anatomicallymodern humans in Africa ~130 KYA • In Israel by ~90 KYA Omo I, Ethiopia, ~130 KYA

37. Origins of modern humans (2) • Modern human behaviourstarts to develop in Africa after ~80 KYA • By ~50 KYA, features such as complex tools and long-distance trading are established in Africa The first art? Inscribed ochre, South Africa, ~77 KYA

38. Expansions of fully modern humans • Two expansions: • Middle Stone Age technology in Australia ~50 KYA • Upper Palaeolithic technology in Israel ~47 KYA Lake Mungo 3, Australia, ~40 KYA

39. the Upper Paleolithic period • In the Upper Paleolithic period: • Neanderthal man disappears • and is replaced by a variety of Homo sapiens

40. Routes of migration?archaeological evidence Upper Paleolithic ~130 KYA Middle Stone Age

41. Strengths and weaknesses of the fossil/archaeological records • Major source of information for most of the time period • Only source for extinct species • Dates can be reliable and precise • need suitable material, C calibration required 14

42. Mixing or replacement?

43. Human genetic diversity is low

44. Modern human mtDNA is distinct from Neanderthal mtDNA Krings et al. (1997) Cell90, 19-30

45. Nature Genetics  33, 266 - 275 (2003) The application of molecular genetic approaches to the study of human evolutionL. Luca Cavalli-Sforza1 & Marcus W. Feldman2

46. Haploid markers from mitochondrial DNA and the Y chromosome have proven invaluable for generating a standard model for evolution of modern humans • earlier research on protein polymorphisms • Co-evolution of genes with language and some slowly evolving cultural traits, together with the genetic evolution

47. Evolutionary events affecting genomic variation (1) • All genetic variation is caused by mutations • The most common and most useful for many purposes are SNPs • which can be detected by DNA sequencing

48. Evolutionary events affecting genomic variation (2) • Allelic frequencies change in populations owing to two factors: • natural selection: • population variation among individual genotypes in their probabilities of survival and/or reproduction, random genetic drift • next generation • Both natural selection and genetic drift can ultimately lead to the elimination or fixation of a particular allele • In the presence of mutation and in the absence of selection: • neutral conditions: • the rate of neutral evolution of a finite population is equal to the mutation rate!

49. Evolutionary events affecting genomic variation (3) • The earliest evidence of selection : • heterozygotes of the hemoglobin A/S • polymorphism have greater resistance to malaria than do AA or SS homozygotes • G6PD locus: • resistance to malaria

50. Evolutionary events affecting genomic variation (4) • Strong directional selection : for FOXP2 • a two amino-acid difference between the human protein and in primates • selectively important for the evolution of speech and language in modern humans