[South Asians should be viewed not as a single population but as thousands of distinct groups reinforced by cultural practices that promote marrying within one’s community. Although recent changes to cultural norms have resulted in more marriages between members of different groups like castes or subcastes, especially in some urban areas, gene flow between populations was restricted for millenniums, the authors report.]
By
Steph Yin
 |
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Gujjar
tribespeople in Kashmir. The group is among 14 others in South Asia that has
over a
million
people but probably started with major genetic contributions from just 100
people
or fewer. Credit Rekha Gill/Getty Images
|
In certain states in southern India,
anesthesiologists know to ask anyone undergoing surgery whether they belong to
the Vysya, a regional group traditionally associated with traders and
businesspeople.
Anecdotally, medical workers know that some
people with Vysya ancestry — who live primarily in Andhra Pradesh and Telangana
— have had fatal responses to common muscle relaxants, so doctors will use a
different combination of drugs.
The Vysya may have other medical predispositions
that have yet to be characterized — as may hundreds of other subpopulations
across South Asia, according to a study published in Nature Genetics on Monday.
The researchers suspect that many such medical conditions are related to how
these groups have stayed genetically separate while living side by side for
thousands of years.
South Asians should be viewed not as a single
population but as thousands of distinct groups reinforced by cultural practices
that promote marrying within one’s community. Although recent changes to
cultural norms have resulted in more marriages between members of different
groups like castes or subcastes, especially in some urban areas, gene flow
between populations was restricted for millenniums, the authors report.
Marriage within a limited group, or endogamy,
has created millions of people who are susceptible to recessive diseases, which
develop only when a child inherits a disease-carrying gene from both parents,
said Kumarasamy Thangaraj, an author of the study and a senior scientist at the
Center for Cellular and Molecular Biology in Hyderabad.
Along with David Reich, a geneticist at
Harvard Medical School, Dr. Thangaraj led an effort to analyze data from more
than 2,800 individuals belonging to more than 260 distinct South Asian groups
organized around caste, geography, family ties, language, religion and other
factors. Of these, 81 groups had losses of genetic variation more extreme than
those found in Ashkenazi Jews and Finns, groups with high rates of recessive
disease because of genetic isolation.
In previous studies, Dr. Reich, Dr. Thangaraj
and colleagues found that social groups in South Asia mixed between around
4,000 and 2,000 years ago. After that, the solidification of India’s caste
system resulted in a shift toward endogamy. “You can see writ in the genome the
effects of this intense endogamy,” Dr. Reich said.
Today, South Asia consists of around 5,000
anthropologically well-defined groups. Over 15 years, the researchers collected
DNA from people belonging to a broad swath of these groups, resulting in a rich
set of genetic data that pushes beyond the field’s focus on individuals of
European ancestry, Dr. Reich said.
The scientists then looked at something
called the founder effect. When a population originates from a small group of
founders that bred only with each other, certain genetic variants can become
amplified, more so than in a larger starting population with more gene
exchange.
Most people carry some disease-associated
mutations that have no effect because they’re present only in one parent’s
genes. In an endogamous group, however, it’s more likely that two individuals
carry the same mutation from a common founder. If they reproduce, their
offspring have a higher risk of inheriting that disease.
Rare conditions are therefore
disproportionately common in populations with strong founder events. Among
Finns, for instance, congenital nephrotic syndrome, a relatively rare kidney
disease, is uniquely prevalent. Similarly, Ashkenazi Jews are often screened
for diseases like cystic fibrosiss or Gaucher disease.
To measure the strength of different founder
events, Dr. Reich and Dr. Thangaraj’s team looked for long stretches of DNA
shared between individuals from the same subgroups. More shared sequences
indicated a stronger founder event.
The strongest of these founder groups most
likely started with major genetic contributions from just 100 people or fewer.
Today, 14 groups with these genetic profiles in South Asia have estimated
census sizes of over one million. These include the Gujjar, from Jammu and
Kashmir; the Baniyas, from Uttar Pradesh; and the Pattapu Kapu, from Andhra
Pradesh. All of these groups have estimated founder effects about 10 times as
strong as those of Finns and Ashkenazi Jews, which suggests the South Asian
groups have “just as many, or more, recessive diseases,” said Dr. Reich, who is
of Ashkenazi Jewish heritage himself.
The next step, the authors say, is to map out
and study the genetic origins of diseases prevalent in different groups. As
proof of concept, they screened 12 patients from southern India for a gene
mutation known to cause a joint disease called progressive pseudorheumatoid
dysplasia. Of the six people that had the mutation, five instances could be
traced to founder effects, and one case could be traced to a marriage between
close relatives.
This distinction is important because it’s
well documented that marriage between close relatives can increase the
possibilities of recessive disease. But many South Asians are not yet aware
that they should also look out for genetic risks among broader populations,
said Svati Shah, an associate professor of medicine at Duke University who was
not involved in the research.
“There’s a tendency to think, ‘This will
never happen to me because I will never marry my first cousin,’” Dr. Shah said.
“But that’s not what’s happening here, according to the data.”
There are many other suspected examples of
disease associations that have yet to be systematically studied in South Asia.
Some medical caregivers speculate that people with the surname Reddy may be
more likely to develop a form of arthritis affecting the spine, Dr. Thangaraj
said. Others think people from the Raju community, in southern India, may have
higher incidents of cardiomyopathy, which affects the heart muscle.
If recessive disease mutations are cataloged,
they could potentially be used for prenatal or premarital screening programs,
which can be “immensely powerful,” said Priya Moorjani, an author of the paper
and a postdoctoral researcher at Columbia University.
An example of successful genetic cataloging
can be found in Dor Yeshorim, a Brooklyn-based organization that screens
Ashkenazi and Sephardi Jews for common disease-causing mutations to inform
marriage matchmaking. The program is credited with virtually eliminating new
cases of Tay-Sachs disease, a neurodegenerative disorder, from these
communities.
Beyond rare diseases, groups with founder
effects hold lessons about common diseases and basic biology, said Alan
Shuldiner, a professor of medicine at the University of Maryland and a genetics
researcher for Regeneron Pharmaceuticals, who was not involved in the study. He
and his collaborators have gained new insights into heart disease and Type 2
diabetes, for instance, from studying Old Order Amish.
Scientists often try to manipulate, or knock
out, genes in mice or flies to better understand human disease. But populations
like those found across South Asia provide a powerful opportunity to study how
gene changes manifest naturally in humans. These are “genetic experiments of
nature that have occurred across the planet,” Dr. Shuldiner said.
The sheer number of people and different
groups in South Asia means there’s a huge, untapped opportunity to do
biological and genetic research there, Dr. Reich said.
He suggested that knockouts of almost every
single gene in the genome probably exist in India.
“I would argue that it’s unequal to anywhere
else,” he said.
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