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The analysis of the world's largest set of data on the genome of pregnant women, totaling 141,431 pregnant women in China, uncovered unsuspected associations between genes and birth outcomes, including the birth of twins and the age of the first pregnancy of the woman.
Non-invasive prenatal tests allow doctors to look for abnormal fetal DNA in the mother's blood.
The analysis also allowed researchers to reconstruct the recent movement and mixed marriages of different ethnic groups in China, and promises to help identify genes that make people vulnerable to infectious diseases.
"It's amazing that it's even possible to take these large samples and map the associations to see which genetic variants explain the human traits," said co-author Rasmus Nielsen, professor of integrative biology at the University of California. Berkeley University. computer analysis conducted by BGI researchers in Shenzhen, China.
This is all the more surprising since researchers have sequenced an average of only 10% of each mother's genome, relying on a large number of poor quality genomes to take advantage of less expensive tests to discover new genetic links.
Prospective mothers had provided test blood samples for chromosomal abnormalities in the fetus, mainly Down syndrome. This technique, called cell-free fetal DNA testing, a form of non-invasive prenatal testing, is possible because mothers have DNA from their unborn child that floats in the blood. With the rapid sequencing of firearms, laboratories can break all the DNA floating in the blood and sequence just enough bits to diagnose Down syndrome.
Although not yet widespread in the US, non-invasive prenatal testing is common in China: 70% of these tests worldwide have been performed in China. The mother's blood can be removed quickly and safely, whereas a standard prenatal test in the United States involves amniocentesis or chorionic villus sampling, which requires fetal cells from the uterus and may harm the fetus.
The maternity wards paid BGI for these tests, but obtained informed consent from each mother to also analyze partially sequenced genomes for research purposes, while maintaining anonymity. All the analyzes were done in China and the data is hosted in the China National GeneBank.
The analysis of the data revealed, for example, that the variation of a gene called NRG1 is related to a greater or lesser incidence of twins. A variant of the gene is more common in mothers of twins and is associated with hyperthyroidism, tightening the link between thyroid function and twinning that had previously been observed in mice.
A variant of another gene, EMB, was associated with older mothers who were mothers for the first time.
The analysis also extracted several genes that had never been associated with body mass index and size.
Perhaps the most interesting, Nielsen said, is that sequencing all the DNA in the mother's blood tells us about the viruses that circulate in the body, and therefore about the link between viruses and the genes that determine susceptibility to the disease.
A variation of a gene, for example, was associated with a higher concentration of herpesvirus 6 in a mother's blood. Herpesvirus 6 is the most common cause of relatively mild skin rash called roseola, but a high "viral load" correlates with more serious symptoms. People with Alzheimer's disease also have higher levels of herpes virus 6 in their brains.
"Most people are infected with the herpes virus 6 at some point in their lives, but some people seem less affected than others. We have now found a human genetic variant that helps control the severity of the infection, "Nielsen said. "It's very interesting because we do not know much about the genetic variants that control why some people seem more likely to be infected with a virus and not others."
More correlations remain to be discovered. To date, the BGI team has sequenced the genomes of more than 3 million pregnant women, largely with information on the health of mothers and babies, which can be used to search for genetic associations.
"If you have these genotypes and you compare them to the phenotypes, that's something you can measure, you can find genetic variants that explain the human traits," said Xun Xu, leader of the BGI team and author study.
Nielsen, Xu, Siyang Liu and other BGI colleagues will report the first results of the October 4 analysis in the newspaper Cell.
Imputed sequencing
To find genes associated with human traits – for example, height and weight – researchers typically sequencing a small number of genomes – hundreds to thousands – and analyzing genomes for sequence variations that are more common. in people with this trait. The best solution now is to sequence each genome 60 times to ensure accuracy given the errors inherent in the sequencing process. Even if each genome is sequenced barely 20 times, which is good but not great, it is still expensive.
The new study relies only on partial genomes – less expensive to obtain – but in very large numbers. On average, about one-tenth of each mother's genome has been sequenced, which is all that is needed for a doctor to diagnose a chromosomal abnormality in the fetus. For example, Down syndrome, or trisomy 21, is caused by three copies of chromosome 21 instead of two. A single round of sequencing is sufficient to determine if some genes are 50% more common than normal, indicating an additional chromosome.
But partial genomes can also mean a lot to researchers, said Nielsen.
Think of restoring a lost book from thousands of copies prone to errors, complicated by the fact that you only have about 10% of each copy. By searching for overlaps and deducting words from context – called imputation – you can reconstruct a lost manuscript.
By reconstructing partial genomes, scientists have another important set of data: all the complete human genomes sequenced to date, with all of their individual variations.
Evidence that imputation using more than 141,000 partial genomes works is that the reconstituted geographical distribution in China of minority groups and dominant Han Chinese reflects the population movements known in the country over the past 100 years.
"Because the size of the sample is so large, we can be aware of recent population movements, including offshoring resulting from Chinese government policies," said Nielsen. Many populations of Han Chinese living in western China are more closely related to the populations of the major cities of the east coast, for example, reflecting the displacement of a large number of people in the countryside sparsely populated
The researchers also discovered that many Chinese had common genetic variants among Indians, Southeast Asians and, along the route of the ancient Silk Road, the Europeans.
Nielsen is currently working with her colleagues at BGI on the genome analysis of 1 million Chinese women who have had a non-invasive prenatal test.
The main collaborators of Nielsen and Xu are Siyang Liu, Xin Jin and Jian Wang from BGI in Shenzhen and Anders Albrechtsen from the University of Copenhagen in Denmark. The work was funded by the Natural Science Foundation of Guangdong Province (China), the University of China and the Danish Innovation Fund.
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