Genetic History of India

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Genetic History of India Dec 27, 2021 22:36:43 GMT

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Post by Admin on Dec 27, 2021 22:36:43 GMT

Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences

We report the sequences of 1,244 human Y chromosomes
randomly ascertained from 26 worldwide populations by
the 1000 Genomes Project. We discovered more than
65,000 variants, including single-nucleotide variants,
multiple-nucleotide variants, insertions and deletions,
short tandem repeats, and copy number variants. Of these,
copy number variants contribute the greatest predicted
functional impact. We constructed a calibrated phylogenetic
tree on the basis of binary single-nucleotide variants and
projected the more complex variants onto it, estimating the
number of mutations for each class. Our phylogeny shows
bursts of extreme expansion in male numbers that have
occurred independently among each of the five continental
superpopulations examined, at times of known migrations
and technological innovations.
The Y chromosome bears a unique record of human history owing
to its male-specific inheritance and the absence of crossover for
most of its length, which together link it completely to male phenotype
and behavior1. Previous studies have demonstrated the
value of full sequences for characterizing and calibrating the human
Y-chromosome phylogeny2,3. These studies have led to insights into
male demography, but further work is needed to more comprehensively
describe the range of Y-chromosome variation, including classes
of variation more complex than single-nucleotide variants (SNVs);
to investigate the mutational processes operating in the different
classes; and to determine the relative roles of selection4 and demography5
in shaping Y-chromosome variation. The role of demography
has risen to prominence with reports of male-specific bottlenecks
in several geographical areas after 10 thousand years ago (kya)5–7,
at times putatively associated with the spread of farming5 or Bronze
Age culture6. With improved calibration of the Y-chromosome
SNV mutation rate8–10 and, consequently, more secure dating
of relevant features of the Y-chromosome phylogeny, it is now possible
to hone such interpretations.
We have conducted a comprehensive analysis of Y-chromosome
variation using the largest extant sequence-based survey of global
genetic variation—phase 3 of the 1000 Genomes Project11. We have
documented the extent of and biological processes acting on five
types of genetic variation, and we have generated new insights into
the history of human males.

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Genetic History of India Dec 28, 2021 3:06:15 GMT

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Post by Admin on Dec 28, 2021 3:06:15 GMT

RESULTS
Data set
Our data set comprises 1,244 Y chromosomes sampled from 26 populations
(Supplementary Table 1) and sequenced to a median haploid
coverage of 4.3×. Reads were mapped to the GRCh37 human reference
assembly used by phase 3 of the 1000 Genomes Project11 and to the
GRCh38 reference for our analysis of short tandem repeats (STRs).
We used multiple haploid-tailored methods to call variants and generate
call sets containing more than 65,000 variants of five types,
including SNVs (Supplementary Fig. 1 and Supplementary Tables 2
and 3), multiple-nucleotide variants (MNVs), short insertions and
deletions (indels), copy number variants (CNVs) (Supplementary
Figs. 2–12), and STRs (Supplementary Tables 4–6). We also identified
karyotype variation, which included one instance of 47,XXY and
several mosaics of the karyotypes 46,XY and 45,X (Supplementary
Table 7). We applied stringent quality control to meet the Project’s
requirement of a false discovery rate (FDR) <5% for SNVs, indels and
MNVs, and CNVs. In our validation analysis with independent data
sets, the genotype concordance was greater than 99% for SNVs and
was 86–97% for more complex variants (Table 1).


Table 1 Y-chromosome variants discovered in 1,244 males
Variant type Number FDR (%) Concordance (%)
SNVs 60,555 3.9 99.6
Indels and MNVs 1,427 3.6 96.4
CNVs 110 2.7 86
STRs 3,253 NA 89–97
The concordance shown is with independent genotype calls, and the CNVs considered
were those computationally inferred using GenomeSTRiP. FDR, false discovery rate;
NA, not available

To construct a set of putative SNVs, we generated six distinct call
sets, which we input to a consensus genotype caller. In an iterative
process, we leveraged the phylogeny to tune the final genotype calling
strategy. We used similar methods for MNVs and indels, and we ran
HipSTR to call STRs (Supplementary Note).
We discovered CNVs in the sequence data using two approaches,
GenomeSTRiP12 and CnvHitSeq13 (Supplementary Note), and we validated
calls using array comparative genomic hybridization (aCGH),
supplemented by FISH on DNA fibers (fiber-FISH) in a few cases
(Supplementary Figs. 8 and 9, and Supplementary Note). In Figure 1,
we illustrate a representative large deletion, which we discovered in
a single individual using GenomeSTRiP (Fig. 1b). We validated its
presence by aCGH (Fig. 1c) and ascertained its structure with fiberFISH
(Fig. 1d). Notably, the event that gave rise to this variant was not
a simple recombination between the segmental duplication elements
it partially encompasses (Fig. 1a,d).

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Genetic History of India Dec 28, 2021 4:04:33 GMT

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Post by Admin on Dec 28, 2021 4:04:33 GMT

Phylogeny
We identified each individual’s Y-chromosome haplogroup
(Supplementary Tables 8 and 9, and Supplementary Data)
and constructed a maximum-likelihood phylogenetic tree using
60,555 biallelic SNVs derived from 10.3 Mb of accessible DNA
(Fig. 2, Supplementary Figs. 13–17, Supplementary Note, and
Supplementary Data). Our tree recapitulates and refines the expected
structure2,3,5, with all but two major haplogroups from A0 through
T represented. The only haplogroups absent are M and S, both subgroups
of K2b1 that are largely specific to New Guinea, which was
not included in the 1000 Genomes Project. Notably, the branching
patterns of several lineages suggest extreme expansions ~50–55 kya
and also within the last few millennia. We investigated these later
expansions in some detail and describe our findings below.
When the tree is calibrated with a mutation rate estimate of
0.76 × 10−9 mutations per base pair per year9, the time to the most
recent common ancestor (TMRCA) of the tree is ~190,000 years, but
we consider the implications of alternative mutation rate estimates
below. Of the clades resulting from the four deepest branching events,
all but one are exclusive to Africa, and the TMRCA of all non-African
lineages (that is, the TMRCA of haplogroups DE and CF) is ~76,000
years (Fig. 1, Supplementary Figs. 18 and 19, Supplementary
Table 10, and Supplementary Note). We saw a notable increase in
the number of lineages outside Africa ~50–55 kya, perhaps reflecting
the geographical expansion and differentiation of Eurasian populations
as they settled the vast expanse of these continents. Consistent
with previous proposals14, a parsimonious interpretation of the
phylogeny is that the predominant African haplogroup, haplogroup E,
arose outside the continent. This model of geographical segregation
within the CT clade requires just one continental haplogroup
exchange (E to Africa), rather than three (D, C, and F out of Africa).
Furthermore, the timing of this putative return to Africa—between
the emergence of haplogroup E and its differentiation within Africa
by 58 kya—is consistent with proposals, based on non–Y chromosome data,
of abundant gene flow between Africa and nearby
regions of Asia 50–80 kya15.

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Genetic History of India Dec 28, 2021 19:15:18 GMT

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Post by Admin on Dec 28, 2021 19:15:18 GMT

Three new features of the phylogeny underscore the importance of
South and Southeast Asia as likely locations where lineages currently
distributed throughout Eurasia first diversified (Supplementary
Note). First, we observed in a Vietnamese individual a rare F lineage
that is an outgroup for the rest of the megahaplogroup (Fig. 1 and
Supplementary Fig. 14b). The sequence for this individual includes
the derived allele for 147 SNVs shared by and specific to the 857 F
chromosomes in our sample, but the lineage split off from the rest
of the group ~55 kya. This finding enabled us to define a new megagroup,
GHIJK-M3658, whose subclades include the vast majority of
the world’s non-African males1. Second, we identified in 12 South
Asian individuals a new clade, here designated H0, that split from
the rest of haplogroup H ~51 kya (Supplementary Fig. 14b). This
new structure highlights the ancient diversity within the haplogroup
and requires a more inclusive redefinition using, for example, the
deeper SNV M2713, a G>A mutation at 6,855,809 bp in the GRCh37
reference. Third, a lineage carried by a South Asian Telugu individual,
HG03742, enabled us to refine early differentiation within the K2a
clade ~50 kya (Fig. 1 and Supplementary Figs. 14d and 15). Using the
high resolving power of the SNVs in our phylogeny, we determined
that this lineage split off from the branch leading to haplogroups
N and O (NO) not long after the ancestors of two individuals with
well-known ancient DNA (aDNA) sequences did. Ust’-Ishim9 and
Oase1 (ref. 16) lived, respectively, in western Siberia 43–47 kya and
in Romania 37–42 kya. The Y chromosomes of these individuals join that of HG03742
in sharing with haplogroup NO the derived T allele at M2308 (GRCh37 Y: 7,690,182 bp),
and the modern sample shares just four additional mutations with the NO clade.

Figure 2
Y-chromosome phylogeny and haplogroup distribution. Branch lengths are drawn proportional to the estimated times between successive splits, with the most ancient division occurring ~190 kya. Colored triangles represent the major clades, and the width of each base is proportional to one less than the corresponding sample size. We modeled expansions within eight of the major haplogroups (circled) (Figure 4), and dotted triangles represent the ages and sample sizes of the expanding lineages. (Inset) World map indicating, for each of the 26 populations, the geographic source, sample size, and haplogroup distribution.

Last Edit: Dec 28, 2021 19:24:24 GMT by Admin

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Genetic History of India Dec 28, 2021 20:39:28 GMT

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Post by Admin on Dec 28, 2021 20:39:28 GMT

Mutations
To map each SNV to a branch (or branches) of the phylogeny, we first partitioned the tree into eight overlapping subtrees (Supplementary Fig. 13). Within each subtree, we provisionally assigned each SNV to the internal branch constituting the minimum superset of carriers of one allele or the other, designating the derived state to the allele specific to this clade. When no member of the clade bore the ancestral allele, we deemed the site compatible with the subtree and assigned the SNV to the branch (Supplementary Note and Supplementary Data File). Most SNVs (94%) mapped to a single branch of the phylogeny, corresponding to a single mutation event during the Y-chromosome history captured by this tree. We projected the other variants onto the tree to infer the number of mutations associated with each (Fig. 3a).

Figure 3
Mutation events. (a) Bar plots show the percentage of each variant type stratum associated with 1, 2, 3–10, or more mutations across the phylogeny. (b) For STRs, scatter plots show the logarithm of the number of mutation events versus major allele length, stratified by motif length and the number of interruptions to the repeat structure. We have plotted regression lines for categories with at least 10 data points, and we have omitted from the plots 44 STRs with motif lengths greater than four and 91 STRs whose mutation rate estimates were equal to the minimum threshold of 10−5 mutations per generation.

Supplementary Figure 10 summarizes our workflow to count the number of independent mutation events associated with each CNV (Supplementary Note). We found that 39% of CNVs have mutated multiple times, a much higher proportion than SNVs (Fig. 3a and Supplementary Data File). CNVs can arise by several different mutation mechanisms, one of which is homologous recombination between misaligned repeated sequences. This mechanism is particularly susceptible to recurrent mutations17 but, in comparing CNVs associated with repeated sequences to those that are not repeat-associated, we did not observe a significant difference in the proportion that have mutated multiple times (Mann-Whitney two-sided test). We did, however, observe that repeat-associated CNVs tend to be longer (p = 0.01).

We inferred more than six independent mutation events for each of three CNVs. One in particular stood out with 154 events. An apparent CNV hotspot spans a gene-free stretch of the chromosome’s long arm at GRCh37 Y:22,216,565–22,512,935. The region includes two arrays of long terminal repeat 12B (LTR12B) elements that together harbor 48 of the genome’s 211 copies (23%). In principle, our inference of numerous independent mutations could have been due to a “shadowing” effect from LTR12B elements elsewhere in the genome. That is, mismapping sequencing reads, and cross-hybridizing CGH probes, can lead to false inference of variation. But, in a phylogenetic analysis of all 211 LTR12B elements (Supplementary Figure 11), those within the putative CNV hotspot formed a pure monophyletic clade, demonstrating that the copy-number signal was genuine. The CNV has no predicted functional consequence.

Short tandem repeats (STRs) constituted the most mutable variant class, with a median of 16 mutations per locus and an average mutation rate of 3.9 × 10−4 mutations per generation. Assuming a generation time of 30 years, this equates to 1.3 × 10−5 mutations per year. Allele length explains more than half the variance of the log mutation rate for uninterrupted STRs. Longer STRs mutate more rapidly, and, conditional on allele length, mutability decreases when the repeat structure is interrupted, with a general trend toward slower mutations rates for STRs with more interruptions (Fig. 3b). Please see our Y-STR companion paper for more details18.