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The genetic makings of South Asia
Mait Metspalu1, Mayukh Mondal1 and Gyaneshwer Chaubey1,2
South Asia is home for more than a billion people culturally
structured into innumerable groups practicing different levels
of endogamy. Linguistically South Asia is broadly
characterized by four major language families which has
served as access way for disentangling the genetic makings of
South Asia. In this review we shall give brief account on the
recent developments in the field. Advances are made in two
fronts simultaneously. Whole genome characterisation of
many extant South Asians paint the picture of the genetic
diversity and its implications to health-care. On the other hand
ancient DNA studies, which are finally reaching South Asia,
provide new incites to the demographic history of the
subcontinent. Before the spread of agriculture, South Asia
was likely inhabited by hunter-gatherer groups deriving much
of their ancestry from a population that split from the rest of
humanity soon after expanding from Africa. Early Iranian
agriculturalists mixing with these local hunter-gatherers
probably formed the population that flourished during the
blossoming of the Indus Valley Civilisation. Further admixture
with the still persisting HG groups and population(s) from the
Eurasian Steppe, formed the two ancestral populations (ANI
and ASI), the north-south mixing pattern of whom is known
today as the ‘Indian Cline’. Studies on natural selection in
South Asia have so far revealed strong signals of sweeps that
are shared with West Eurasians. Future studies will have to
fully unlock the aDNA promise for South Asia.
Addresses
1
Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu,
Estonia
2
Cytogenetics Laboratory, Department of Zoology, Banaras Hindu
University, Varanasi, India
Current Opinion in Genetics & Development 2018, 53:128–133
This review comes from a themed issue on Genetics of human
origins
Edited by Lluis Quintana-Murci and Brenna Henn
https://doi.org/10.1016/j.gde.2018.09.003
0959-437X/ã 2018 Elsevier Ltd. All rights reserved.
Out-of-Africa and into South Asia
Recent studies harnessing the power of analysing com-
plete genomes from many populations worldwide have
established that most if not all humans outside Africa
descend from the main Out-of-Africa (OoA) expansion
Current Opinion in Genetics & Development 2018, 53:128–133
some 50 thousand years ago (kya) [1,2,3,4]. Given the
documented admixture of all non-Africans with Nean-
derthals and ample archaeological evidence of Middle
Palaeolithic hominin presence in South Asia well before
the main OoA [5], it remains of interest to explore the vast
and structured genetic landscape of South Asia for ves-
tiges of potential additional archaic admixture events.
Indeed, it was recently suggested that South and South-
east Asians do carry a small proportion of genetic ancestry
from an unknown extinct hominin [4]. While, these
conclusions were not replicated in different datasets
[6], the discussion is still open [7]. In a different bid,
using a haplotype sharing pattern-based approach, Pagani
et al. [3] claimed that at least 2% of the genomes of
modern Papuans originate in an earlier OoA (xOoA) that
split from the rest of Africans around 120 kya. The
possibility of an earlier OoA is circumstantially backed
up by evidence for admixture of modern humans into
Neanderthals long before OoA [8,9] and the growing
archaeological body of evidence of modern human pres-
ence in Arabia [10] and East and Southeast Asia well
before 60 kya [11]. While the parallel studies [1,2] did
not find evidence for genomic survival of xOoA in the
Papuans, they noted that a small percentage of such
ancestry may go unnoticed by the methods used in these
studies. If xOoA is true, South Asia would be a prime
place for vestiges of it to have survived. So far such
evidence has not been presented.
Formation of the current South Asian
populace — the great mix
The rich literature on human mitochondrial DNA and
Y chromosome phylogenetics/phylogeography in South
Asia [12–18] is largely in agreement highlighting the
first, presence of deep rooting autochthonous genetic
component and second, shared genetic component
with West Eurasians. This western component
decreases in frequency from northwest (40%) toward
south and east (<10%) and is more prevalent in high-
caste groups (e.g. Brahmins). While it was evident that
this genetic sharing originated likely in different time
horizons, it was difficult to examine/test-specific
admixture scenarios.
In 2009 the seminal study by Reich et al. [19] turned the
page by conducting the first genome-wide survey in
South Asia. In parallel with creating a new toolkit for
population genetics analyses [20], this study revealed on
the genomic level that most South Asian populations can
be described as mixtures of different proportions of two
ancestral populations - ancestral Northern and Southern
Indians - ANI and ASI - of which the former is genetically
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 The genetic makings of South Asia Metspalu, Mondal and Chaubey 129

closer to West Eurasian genetic variation that to ASI. ASI Figure 1

in turn is as distant from West Eurasian branch than from
East Asian (or the two latter from each other). The ANI (a)
component has a familiar geographical spread pattern in
South Asia decreasing from the northwest - named in
Reich et al. the ‘Indian Cline’. Metspalu et al. [21]
extended this work by adding data on another 30 Indian
populations. While confirming the existence of the two
components, an attempt was made to date them with an
ad hoc approach relying on haplotype diversity. Proper
dating of the ANI ASI admixture event, measuring the
decay of linkage disequilibrium generated by the admix-
ture [22], was performed by Moorjani et al. [23] which
resulted in mixture dates ranging from about 1900 to
4200 years ago (2200 BCE–100 CE). Importantly, after
this period of mixing Indian populations apparently
shifted toward endogamy [23,24].
(b)
The myriad of recent ground-breaking ancient DNA
studies have reshaped our understanding of the demo-
graphic history particularly of West Eurasia. Unfortu-
nately the climatic conditions in South Asia make it
difficult for human (skeletal) remains, let alone DNA
in the remains, to survive for thousands (even hundreds)
of years. Nevertheless, after it was shown that the spread
of agriculture in Europe was a result of the demic
diffusion of early Anatolian farmers, it was discovered
that the spread of agriculture to South Asia was mediated
by a genetically completely different farmer population
in the Zagros mountains in contemporary Iran (IF)
[25,26,27]. The ANI-ASI cline itself was interpreted
as a mixture of three components genetically related to (c)
Iranian agriculturalists, Onge and Early and Middle
Bronze Age Steppe populations (Steppe_EMBA) [25].
The first ever autosomal aDNA from South Asia comes
from Northern Pakistan (Swat Valley, early Iron Age)
[28]. This study presented altogether 362 aDNA sam-
ples from the broad South and Central Asia and contrib-
utes substantially to our understanding of the evolution-
ary past of South and Central Asia. The study redefines
the three genetic strata that form the basis of the Indian
Cline. The Indus Periphery (IP) component is composed
of (varying proportions of): first, IF, second, Ancient
Ancestral South Asians (AASI), which represents an
ancient branch of human genetic variation in Asia arising
from a population split contemporaneous with the splits Current Opinion in Genetics & Development
of East Asian, Onge and Australian Aboriginal ancestors
(in accordance with [4,29]) and third, West_Siberian A sketch of the peopling history of South Asia. Depicting the full
Hunter gatherers (WS_HG). The authors argue that IP complexity of available reconstructions is not attempted. Placing of
could have formed the genetic base of the Indus Valley population labels does not indicate precise geographic location or
Civilization (IVC). Upon the collapse of the IVC IP range of the population in question. Rather we aim to highlight the
essentials of the recent advancements in the field. We divide the
contributes to the formation of both ASI and ANI. ASI
scenario into three time horizons: Panels (a) before 10 000 BCE (pre
is formed as IP admixes further with AASI. ANI in turn agriculture era.); (b) 10 000 BCE to 3000 BCE (agriculture era) and (c)
forms when IP admixes with the incoming Middle and 3000 BCE to prehistoric era/modern era. (iron age).
Late Bronze Age Steppe (Steppe_MLBA) component,
(rather than the Steppe_EMBA groups suggested ear-
lier) (Figure 1).

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130 Genetics of human origins
The two lesser sisters
The vast majority of South Asians speak languages belong-
ing to either Indo-European or Dravidian families and can,
from the genetic point of view, be described within the
concept of the ‘Indian Cline’ described in the previous
section. However around 20 million South Asians in total,
speak either Munda languages of the Austro-Asiatic family
or languages of the Tibeto-Burman phylum. Although
many scenarios have been put forward in the past, it is
by now quite clear that the Munda speakers of India are
derived from a dispersal from southeast Asia followed by
extensive sex-specific admixture with local Indian popula-
tions [30,31]. The expansion in Southeast Asia is also
documented using aDNA [32]. Dating of the arrival of
the Austro-Asiatic speakers in South Asia-based on Y
chromosome haplogroup O2a1-M95 expansion estimates
yielded dates between 3000 and 2000 BCE [30]. However,
admixture LD decay-based approach on genome-wide data
suggests the admixture between South Asian and incoming
Austro-Asiatic speakers occurred slightly later between
1800 and 0 BCE (Tätte et al. submitted). It is interesting
that while the mtDNA variants of the Mundas are
completely South Asian, the Y chromosome variation is
dominated at >60% by haplogroup O2a which is phylogeo-
graphically nested in East Asian-specific paternal lineages.
Genome wide the Munda derive ca 20% of their genetic
ancestry from Southeast Asia and the Lao people stand out
as the best surrogate for the source population (Tätte et al.
submitted). It is also interesting to note that the Southeast
Asian-specific ancestry contribution is larger among the
South Munda than North Munda. Furthermore, the Indian
component in Munda contains less West Eurasian-like
genetic variation (and hence more AASI) than ASI (or
Paniya as the best surrogate for ASI). Together this is
consistent with differential Southeast Asian contribution
to as yet forming ASI population(s) where the relative
contribution of AASI was higher than in the finally formed
ASI (Tätte et al. submitted; [28]).
The Khasi represent a separate branch of the Austro-
Asiatic language family (Khasi-Aslian), differ genetically
from Munda substantially and resemble more the Tibeto-
Burman speakers of India albeit slightly larger Indian
ancestry component [31].
In India, the speakers of Tibeto-Burman (TB) languages
live in the Seven Sisters States in Northeast India and in
the very north of the country. Genetically they show a
clear East Asian origin [19,21] and around 20% of subse-
quent admixture with South Asians within the last
1000 years [33]. The genetic flavour of East Asia in TB
is different from that in Munda speakers as the best
surrogates for the East Asian admixing component are
contemporary Han Chinese [33].
The foothills of Himalaya hosts a wide range of ethnic
groups with linguistic, ethnic and genetic diversity.
Current Opinion in Genetics & Development 2018, 53:128–133
Among them, one of the largest and most notable one
are Tharus, who are believed to be the aboriginal popu-
lation of Tarai region. Analysis by using haploid and
diploid markers on this population suggested their expan-
sions in three different directions from Terai, followed by
extensive admixture with locals. Moreover, in spite of the
profound intra ethnic admixtures, the genetic signatures
linking all the Tharu groups was evident [34].
Sex-specific admixtures
Because of small effective population size and the fact
that the lack of recombination renders mtDNA and NRY
chromosome effectively single loci, these systems are not
ideal for studying migrations of populations. Neverthe-
less, sex-specific genetic diversity patterns can reveal
interesting cases of population social structure [35] and
sex-specific admixture patterns as discussed before for
the case of the Munda and reviewed more generally in
[36]. Further studies including comparisons of autosomal
to X chromosome genetic variation will have to reveal the
details of evolutionary history (sex-specific migration,
sex-specific ethnically non-random mating, effects of
random genetic drift owing to small Ne of mtDNA) that
led to current sex-specific pattern of Southeast Asian
genetic contribution into the Munda.
Case studies of change of language or genes
While language family is generally a good proxy for
genetic structure of South Asian populations, there are
several cases where such prediction is spectacularly
wrong. The largest tribal group in India — the Dravidic
speaking Gond — seem to share more of their genetic
ancestry with the Indian Munda speakers, rather than
with the other Dravidian groups [37]. On the other hand
the Mushars speak a tongue from the Indo-European
group, yet genetically are again similar to Munda speakers
[38]. These are examples of language change - where a
population adopts a new language but retains much of
their genetic legacy, although the genetic history of the
Gond is likely more complex. Contrary example is pro-
vided by the Brahui, who have retained Dravidic lan-
guage while genetically they resemble their geographic
neighbours in Pakistan, far from the geographic realm of
Dravidic languages [39].
Genetic vestiges of more recent immigration
events
In additional to the several prehistorical migratory events,
South Asia has experienced immigration of several ethnic
groups in the more recent past. Among the recent
migrants, Siddis [40], Muslims [41], Jewish [42] and Parsis
[43] have been studied. The Siddis have been brought
by Portuguese traders during the 17th–19th centuries and
sold them to the Nawabs and the Sultans of India to serve
as soldiers and slaves. The genetic analysis of Siddis has
overwhelmingly supported their admixture in last 200–
300 years with 30% Indian and 70% African-specific
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 The genetic makings of South Asia Metspalu, Mondal and Chaubey 131
ancestries [40]. Indian Jews arrived in two major waves,
on which the first arrived to South India (Cochin) during
5th century, whereas second was settled in West India
(Mumbai) during 10th century [42]. In case of another
migrant Parsis, who came from Persia (modern Iran), the
admixture with the local South Asian populations was
minimal in comparison with other historical migrants to
India (Jews and Siddi). The molecular data suggested
longer Runs of Homozygosity (RoH) and their arrival to
South Asia in 7th century [43]. Parsis are genetically
closer to Neolithic Iranians than to modern Iranians, who
have witnessed a more recent wave of admixture from the
Near East [43]. The spread of Islam in South Asia was
predominantly cultural conversion associated with minor
but still detectable levels of gene flow from Iran and
Central Asia, rather than directly from the Arabian Pen-
insula [41].
The smallest ethnoreligious community of Pakistan, the
Kalash, claim ancestry in the Army of Alexander the
Great. Earlier Y chromosomal and autosomal STR studies
found no support for such claims [44,45]. While there is
discussion on the extent and timing of admixture events
in the demographic past of the Kalash, all agree that they
have experienced strong effects of genetic drift likely due
to long-term small population size [46–48].
Natural selection to local environment
As discussed above, in the broadest perspective, the
genetic makeup of South Asians today arises from deep
autochthonous genetic legacy (AASI) and several more
recent admixture waves mostly from the West (Iranian
agriculturalists, Steppe pastoralists). Therefore, our
expectation would be that South Asian populations har-
bour a mix of shared (with West Eurasians) and exclusive
signals of natural selection. This is reflected in the sharing
patterns of selection signals between continental regions
[3,21,49]. Indeed, the two biggest signals of selective
sweeps come from gene variants likely introduced to
South Asia through relatively recent admixture from
the west. These top hits are related with skin pigmenta-
tion [50–52] and lactose tolerance [53]. Accordingly both
have a geographic pattern in South Asia corresponding
broadly to the ‘Indian Cline’. However, it is not immedi-
ately clear if natural selection on these gene variants is in
fact continuing in South Asia or are we detecting (only)
selection that happened before the arrival of these hap-
lotypes in South Asia. Better approaches for selection
testing in South Asia need to be adopted that specifically
take admixture into account and discriminate between
introgressed regions and regions which are specifically
selected in South Asian populations. Among the selection
signals that do show some degree of specificity to South
Asia are genes associated with type 2 diabetes in mainland
India [21] and height-related genes among the Andama-
nese [4].
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Future perspectives
The recent advances in aDNA research have significantly
furthered our understanding of the evolutionary history of
South Asia. However, given the current temporally and
spatially limited aDNA record in South Asia, it is safe to
assume, that significant advances will be made as more
aDNA studies will be published, most importntly from
Gangetic plain. South Asia is thought to have witnessed
up to five distinct agricultural transitions [54], but the
extent to which they were indigenous developments or
the result of either cultural or demic diffusion — or how
they relate to the distribution of the languages — is not
fully resolved. Ultimately the understanding of the
genetic genesis of South Asia is relevant for gaining better
understanding of disease and providing better healthcare.
And in this respect the differences of South Asia from the
more extensively studied parts of the World are important
not only because of different genetic ancestry and large
amount of genetic variation not present in other regions
[55,56], but also social structure that affects kinship
patterns which are relevant for disease. For example there
are 14 populations with population size over one million
who have experienced more extreme founder effects than
the usual examples from Europe such as the Finns and
Ashkenazi Jews who have extensively been studied for
recessive diseases [56]. Combining the aDNA research
effort and extensive characterisation of extant genetic
variation make possible genetic ancestry aware investiga-
tions of kinship patterns and their role in disease pheno-
types. This direction constitutes a both relevant and
interesting direction of research for the immediate future.
Conflict of interest statement
Nothing declared.
Acknowledgements
M. Met. by Estonian Research Council grant PRG 243 was supported by the
European Union through the European Regional Development Fund
project Centre of Excellence for Genomics and Translational Medicine
Project No. 2014–2020.4.01.15-0012 to the EBC-IG. M.Mon. was supported
by the European Union through the European Regional Development
Fund (Project No. 2014-2020.4.01.16-0030) to the EBC-IG. G.C. is
supported by the National Geographic Society’s grant for Research and
Exploration (Grant No. HJ3-182R-18) and Estonian Research Council grant
IUT-24-1 to the EBC-IG.
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 The genetic makings of South Asia Metspalu, Mondal and Chaubey 133
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ples from 230 South Asian populations and combines it with published
data to arrive at as yet largest data set of genomic diversity in South Asia.
This data is used to study the population structure of South Asia and
highlight the role of endogamy in promoting population structuring com-
paring to West Eurasian populations. These results have direct implica-
tions for developing better, genomics aware, health-care in South Asia.
Current Opinion in Genetics & Development 2018, 53:128–133