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Reconstructing Ancestral Haplotypes in Isolates : By LEVY ULANOVSKY1, Anat Blumenfeld2, and Susan Slaugenhaupt3,4
1Los Alamos National Laboratory;
2Hadassah University Hospital;
3Harvard Medical School;
4Massachusetts General Hospital Reconstructing Ancestral Haplotypes in Isolates
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Ancestral Haplotypes : Ancestral Haplotypes SNP- vs. STR-based haplotypes;
Panhuman vs. recent bottlenecks;
Mixed vs. isolated populations;
Ashkenazi haplotypes (recent data)
Panhuman Y-SNP haplotypes : Panhuman Y-SNP haplotypes Hammer et al., PNAS vol. 97, p. 6769 (June 6, 2000), scored 18 SNPs on 1,371 Y-chromosomes in apes and 29 human populations from Europe, Middle East and Africa. 19 haplotypes were found. Their estimated ages ranged from tens to hundreds KY. Europe and Mid-East showed similar frequencies of the major haplotypes, different from the Sub-Saharan populations.
Slide 6 : ??? ???????????? ?????? (SNP + STR markers)
Nature 394, p.138, July 9,1998
Thomas, MG; Skorecki K, Ben-Ami H, Parfitt T, Bradman N, Goldstein DB
Panhuman non-Y Haplotypes : Panhuman non-Y Haplotypes In non-Y chromosomes the ancestral panhuman haplotypes have been disrupted by recombination.
Are they still be detectable, perhaps at the range of a few kb or less?
Is it too short for association studies?
Recombination 1 : Recombination 1
Recombination 2 : Recombination 2
Recombination 3 : Recombination 3
Recombination 4 : Recombination 4
Recombination 5 : Recombination 5
Recombination 6 : Recombination 6
Recombination 7 : Recombination 7
Haplotypes in Young Isolated Populations : Haplotypes in Young Isolated Populations Does their young age make their haplotypes much longer and clearer? Their founding bottlenecks are ~ 100 times more recent than panhuman bottlenecks. b) How frequent are they (for statistically significant association with phenotype)?
Ashkenazi Jews’ case : Ashkenazi Jews’ case We have counted all haplotypes on chr. 9q31-33 using 17 STRs in 504 unrelated Ashkenazi chromosomes. Additional ~1,000 chromosomes are being processed.
The data are a byproduct of the mapping of the gene for familial dysautonomia (FD). FD is a rare genetic disease (a recessive neuropathy, Ashkenazi-specific) with 50% survival by age 30 and no known cure.
Of 504 non-FD chromosomes, 52% were represented by as few as 44 identified ancestral haplotypes.
Cluster Example : Cluster Example Chromosomes
A B C D E F G H I J K L M N O P Q R S 8 S58
Haplotype Distribution by Frequency : Haplotype Distribution by Frequency
~ 1,000 More Chromosomes : are in our pipeline. We expect to identify ~100 ancestral haplotypes representing 70%-80% of the sample. We define a haplotype as ‘identified’ if it represents at least 3 (of the 504) chromosomes with identical STR alleles and p < 0.01.
The ~100 extant haplotypes suggest stronger genetic drift than was previously assumed. ~ 1,000 More Chromosomes
SNPs vs. STRs in Isolated Populations : SNPs vs. STRs in Isolated Populations Young isolated population (Quebecois, Icelanders, Ashkenazim, etc.) are ~ 1,000 year old. On this time frame both SNPs and STRs are stable and thus should reflect the same young haplotype mosaic of ~Mb scale. Therefore the presented STR data are relevant for SNP haplotypes.
LD: Single Alleles vs. Haplotypes : LD: Single Alleles vs. Haplotypes The set of extant haplotypes in an isolated population can be viewed as an extremely polymorphic super-marker. In mixed populations it is too polymorphic, while in young isolates the haplotype frequency is high enough and a causative SNP correlates with a haplotype over ~ 1.0 Mb.
By contrast, an allele of a regular marker is shared by several haplotypes. Thus it provides less LD power than a haplotype. In the future, genome-wide ancestral haplotypes may be determined in young isolates. That would offer a useful tool for association studies.
Conclusions: : Conclusions: Most of the Ashkenazi population should be represented by as few as ~ 100 haplotypes.
The average distance between the recombination points is ~ 1.5 Mb.
Knowledge of the ancestral haplotypes may be useful for genome-wide association studies. Information about ancestral haplotypes in young isolates may be very valuable:
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