Human genome diversity: Frequently asked questions Guido Barbujani Dipartimento di Biologia ed Evoluzione, Università di F...
Total size   3 272 480 987(haploid) N of protein-coding genes   22 320 N of RNA-coding genes    9 922 N of gene exons   53...
Human-mouse alignment
Human-chimp alignment Chimp chromosomes 2 and 2a The human genome is very similar to the chimpanzee genome
Phylogenetic tree of human (n=70), chimpanzee (n=30), bonobo (n=5), gorilla (n=11) and orang-utan (n=14), based on 10,000 ...
Genomic estimates of  F ST  for the global human population are    0.12  Human populations display    12% of the maximum...
0.38 0.32 0.12 Genetic diversity among human populations is the lowest  of all primates F ST Geographically-variable selec...
Li et al. (2009) Clinal variation in the geographical space is the rule for human populations Cavalli-Sfdorza et al. (1994)
Methods 1 : Estimating variances from sequence comparisons - TA C GAACATC A GGC - - TA T GAACATC A GGC - - TA T GAACATC G ...
Genetic variances within and between populations Population 1  Population 2  variance between pops. 100% 19% 0%
Independent studies of genetic variances yield very similar results: 85, 5, 10 Lewontin (1972)    17 loci 85% 8% 6% Latter...
What does it mean, in practice? 100% 100% 100% Members of our community are only slightly less different from us than memb...
Mind the numbers Humans and chimps share >98% of their genomes Among the 1.8% differences, 1.7% are fixed differences with...
Methods 2 : Clustering genotypes or haplotypes K=3 K=4 Rosenberg et al., 2002
SNPs Haplotypes CNV Jakobsson et al. (2008) Structure inferred from SNPs and haplotypes differs from that inferred from Co...
Genes, as well as morphology, suggest inconsistent clusterings of genotypes Y chromosome: Romualdi et al. 2002 X chromosom...
Sampling assumptions have a large effect on the apparent structuring
Sampling assumptions have a large effect on the apparent structuring Serre and P ääbo (2004)
ASIP A8818G MATP C374G Genetic variation is discordant across loci
Similar skin colors are due to different combinations of alleles MATP C374G ASIP A8818G
16 completely sequenced genomes  (as of May 1st, 2010)   And 5 more published on May 6th:
Two persons from the same continent may share fewer SNPs than persons of different continents
81% of SNPs cosmopolitan. Alleles present in one continent only: 0.91% in Africa, 0.75% in Asia, practically 0 elsewhere. ...
In  the 117 megabases (Mb) of sequenced exome-containing intervals, the average rate of nucleotide difference between a pa...
Genetic diversity out of Africa is often a subset ot the African genetic diversity   Tishkoff et al. (1998)
LD decreasing with physical distance between loci and with geographic distance from East Africa Jakobsson et al. 2008
Gene diversity declines as a function of distance from Africa Best fit of the model for an African exit 56,000 years ago L...
Patterns of  morphological  and  genetic  variation are compatible with the effects of dispersal from Africa Manica et al....
Models with an African population replacing previous human continental groups explain the data better than any alternative...
<ul><li>The human genome is very similar to the chimpanzee genome </li></ul><ul><li>I ndividual genetic diversity among hu...
100,000 years ago
70,000 years ago
60,000 years ago
30,000 years ago
10,000 years ago
 
<ul><li>In all samples, tests for presence of Neandertal mtDNA </li></ul><ul><li>mtDNA from Vi33-26 and Vi33-16 identical,...
Divergence from modern humans Neandertals  fall inside the variation of present-day humans. Overall divergence greater for...
Segments of Neandertal genome in non-African genomes <ul><li>Statistic: D= Difference in polyorphic alleles  shared  with ...
1. Comparison with the HapMap sequences and 5 newly sequenced individuals 2. No comparison within Eurasia  (Papuan-French-...
Four processes potentially accounting for the data  Between 1 and 4% of the genomes of people in Eurasia are derived from ...
Enza Colonna And if you want to read more about all this  Trends in Genetics , July 2010
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Lisbon genome diversity

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Lisbon genome diversity

  1. 1. Human genome diversity: Frequently asked questions Guido Barbujani Dipartimento di Biologia ed Evoluzione, Università di Ferrara [email_address]
  2. 2. Total size 3 272 480 987(haploid) N of protein-coding genes 22 320 N of RNA-coding genes 9 922 N of gene exons 530 906 N of transcripts 142 707 N of segregating sites 15 040 632 Nucleotide differences with chimp 1.23% Chimp orthologue genes 13 454 Human genes missing in chimp 36 totally, 17 largely Classes of genes with max. differences immune response, reproduction, olfaction A few human genome statistics From www.ensembl.org version 57.37b (Jan. 2010)
  3. 3. Human-mouse alignment
  4. 4. Human-chimp alignment Chimp chromosomes 2 and 2a The human genome is very similar to the chimpanzee genome
  5. 5. Phylogenetic tree of human (n=70), chimpanzee (n=30), bonobo (n=5), gorilla (n=11) and orang-utan (n=14), based on 10,000 bp sequences of a noncoding Xq13.3 region. Kaessmann et al. (2001). Individual genetic diversity among humans is the lowest of all primates
  6. 6. Genomic estimates of F ST for the global human population are  0.12 Human populations display  12% of the maximum possible diversity, given their allele frequencies N of markers Samples F ST Reference 599,356 SNPs 209 individuals from 4 populations: Caucasian, Chinese, Japanese, Yoruba 0.13 Weir et al. 2005 1,034,741 SNPs 71 individuals from 4 populations: Caucasian, Chinese, Japanese, Yoruba 0.10 Weir et al. 2005 1,007,329 SNPs 269 individuals from 4 populations: Caucasian, Chinese, Japanese, Yoruba 0.12 International HapMap Consortium 2005 443,434 SNPs 3845 worldwide distributed individuals 0.052 Auton et al. 2009 2,841,354 SNPs 210 individuals from 4 populations: Caucasian, Chinese, Japanese, Yoruba 0.11 Barreiro et al. 2008 243,855 SNPs 554 individuals from 27 worldwide populations 0.123 Xing et al. 2009 100 Alu insertions 710 individuals from 23 worldwide populations 0.095 Watkins et al. 2008 67 CNVs 270 individuals from 4 populations with ancestry in Europe, Africa or Asia 0.11 Redon et al. 2006
  7. 7. 0.38 0.32 0.12 Genetic diversity among human populations is the lowest of all primates F ST Geographically-variable selection Small population sizes Little gene flow Isolation Stabilizing selection Large population sizes Extensive gene flow Admixture
  8. 8. Li et al. (2009) Clinal variation in the geographical space is the rule for human populations Cavalli-Sfdorza et al. (1994)
  9. 9. Methods 1 : Estimating variances from sequence comparisons - TA C GAACATC A GGC - - TA T GAACATC A GGC - - TA T GAACATC G GGC - Polymorphic DNA sites
  10. 10. Genetic variances within and between populations Population 1 Population 2 variance between pops. 100% 19% 0%
  11. 11. Independent studies of genetic variances yield very similar results: 85, 5, 10 Lewontin (1972) 17 loci 85% 8% 6% Latter (1973) 18 86% 5% 9% Barbujani et al. (1997) 109 85% 5% 10% Jorde et al. (2000) 100 85% 2% 13% Romualdi et al. (2002) 32 83% 8% 9% Rosenberg et al. (2002) 377 93% 3% 4% Excoffier & Hamilton (2003) 377 88% 3% 9% Ramachandran et al. (2005) 17 90% 5% 5% Bastos-Rodriguez et al. (2006) 40 86% 2% 12% Li et al. (2008) 650 000 89% 2% 9% MEDIANA within populations between populations between races or continents 85% 5% 10%
  12. 12. What does it mean, in practice? 100% 100% 100% Members of our community are only slightly less different from us than members of distant populations 85% 85% 85%
  13. 13. Mind the numbers Humans and chimps share >98% of their genomes Among the 1.8% differences, 1.7% are fixed differences within species The remaining fraction, 0.1%, contains all human genomic variation The differences among the main continental groups represent 10% of 0.1% of the total, that is, 0.01% But 0.1% of >3 billion DNA sites means >3 million polymorphic DNA sites (3,213,401 according to Levy et al. 2007)
  14. 14. Methods 2 : Clustering genotypes or haplotypes K=3 K=4 Rosenberg et al., 2002
  15. 15. SNPs Haplotypes CNV Jakobsson et al. (2008) Structure inferred from SNPs and haplotypes differs from that inferred from Copy Number Variation
  16. 16. Genes, as well as morphology, suggest inconsistent clusterings of genotypes Y chromosome: Romualdi et al. 2002 X chromosome: Wilson et al. 2001 377 STR loci: Barbujani and Belle 2006 377 STR loci: Rosenberg et al. 2002 Europe, Ethiopia S. Africa N. Guinea Asia Africa Asia, Europe, Australia, Americas Americas Melanesia Eurasia N Africa N America Maya S. Africa E Africa C Africa Piapoco Suruì Karitiana Kalash W. Eurasia E. Asia Africa Americas Oceania
  17. 17. Sampling assumptions have a large effect on the apparent structuring
  18. 18. Sampling assumptions have a large effect on the apparent structuring Serre and P ääbo (2004)
  19. 19. ASIP A8818G MATP C374G Genetic variation is discordant across loci
  20. 20. Similar skin colors are due to different combinations of alleles MATP C374G ASIP A8818G
  21. 21. 16 completely sequenced genomes (as of May 1st, 2010) And 5 more published on May 6th:
  22. 22. Two persons from the same continent may share fewer SNPs than persons of different continents
  23. 23. 81% of SNPs cosmopolitan. Alleles present in one continent only: 0.91% in Africa, 0.75% in Asia, practically 0 elsewhere. Jakobsson et al. 2008 (525910 SNPs, 396 CNVs)
  24. 24. In the 117 megabases (Mb) of sequenced exome-containing intervals, the average rate of nucleotide difference between a pair of the Bushmen was 1.2 per kb, compared to an average of 1.0 per kb between a European and Asian individual. Schuster et al. (2010) Greater differences between Africans than between European and Asians
  25. 25. Genetic diversity out of Africa is often a subset ot the African genetic diversity Tishkoff et al. (1998)
  26. 26. LD decreasing with physical distance between loci and with geographic distance from East Africa Jakobsson et al. 2008
  27. 27. Gene diversity declines as a function of distance from Africa Best fit of the model for an African exit 56,000 years ago Liu et al. (2006)
  28. 28. Patterns of morphological and genetic variation are compatible with the effects of dispersal from Africa Manica et al. (2007)
  29. 29. Models with an African population replacing previous human continental groups explain the data better than any alternative models Fagundes et al. (2007)
  30. 30. <ul><li>The human genome is very similar to the chimpanzee genome </li></ul><ul><li>I ndividual genetic diversity among humans the lowest of all primates </li></ul><ul><li>Population differences among humans (F ST s) the lowest among primates </li></ul><ul><li>Clinal patterns in the geographical space the rule, not the exception </li></ul><ul><li>Genes, as well as morphology, suggest inconsistent clusterings of genotypes </li></ul><ul><li>Genetic variation discordant across loci </li></ul><ul><li>Similar skin colors due to different combinations of alleles </li></ul><ul><li>Two persons from the same continent may be less similar than persons of different continents </li></ul><ul><li>Greater differences between Africans than between European and Asians </li></ul><ul><li>Alleles in non African populations often a subset of African alleles </li></ul><ul><li>Models with an African population replacing previous human continental groups explain the data better than any alternative models </li></ul><ul><li>Gradients of gene diversity correlated with distance from Africa </li></ul>To make a long story short: So, what happened?
  31. 31. 100,000 years ago
  32. 32. 70,000 years ago
  33. 33. 60,000 years ago
  34. 34. 30,000 years ago
  35. 35. 10,000 years ago
  36. 37. <ul><li>In all samples, tests for presence of Neandertal mtDNA </li></ul><ul><li>mtDNA from Vi33-26 and Vi33-16 identical, but diff(within) < diff(between) </li></ul><ul><li>Between 95% and 99% sequences from non primates </li></ul><ul><li>Enrichment of libraries with enzymes preferentially cutting bacterial genomes </li></ul>Preliminary analyses
  37. 38. Divergence from modern humans Neandertals fall inside the variation of present-day humans. Overall divergence greater for the three Neandertal genomes (modes ~11%), whereas the San mode is ~9% and for the other present-day humans ~8%. For the Neandertals, 13% of windows have a divergence above 20%, whereas this is the case for 2.5% to 3.7% of windows in the current humans
  38. 39. Segments of Neandertal genome in non-African genomes <ul><li>Statistic: D= Difference in polyorphic alleles shared with Neandertals between two humans. </li></ul><ul><li>2. D(Asia-Europe) = -0.53, P=0.25 </li></ul><ul><li>3. D(Europe-Africa) = 4.57, D(Asia-Africa) = 4.81, both P<10 -12 </li></ul><ul><li>4. The greater genetic proximity of Neandertals to Europeans and Asians than to Africans is seen no matter how we subdivide the data: (i) by individual pairs of humans, (ii) by chromosome, (iii) by transitions or transversions, (iv) by hypermutable CpG versus all other sites, (v) by Neandertal sequences shorter or longer than 50 bp . </li></ul><ul><li>5. C ontamination of the Neandertal sequences with non-African DNA? However, the magnitude of contamination necessary to explain the Europe-Africa and Asia-Africa comparisons are both over 10% and thus inconsistent with estimates of contamination in the Neandertal data, all below 1% </li></ul>?
  39. 40. 1. Comparison with the HapMap sequences and 5 newly sequenced individuals 2. No comparison within Eurasia (Papuan-French-Han) or within Africa (Yoruba- San) shows significant skews in D 3. All comparisons of non-Africans and Africans show that the Neandertal is closer to the non-Africans 4. All or almost all the gene flow detected was from Neandertals into modern humans 5. Some old haplotypes most likely owe their presence in non Africans to gene flow from Neandertals
  40. 41. Four processes potentially accounting for the data Between 1 and 4% of the genomes of people in Eurasia are derived from Neandertals 1. From erectus to Neandertal 2. From late Neandertals into the first Europeans 3. From early Neandertals into the first Eurasians 4. Ancient population structure, preserved from before the Neandertal – modern sapiens separation
  41. 42. Enza Colonna And if you want to read more about all this Trends in Genetics , July 2010
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