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Whole-Genome Sequencing of One Patient Identifies Genes Potentially Involved in Preterm Birth

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By Monica Heger

Researchers from Washington University and Vanderbilt University have used whole-genome sequencing on the Illumina GA to identify genes potentially involved in preterm birth, showing that the approach can be used to uncover genes that might play a role in a complex genetic disease.

Justin Fay, assistant professor of genetics at Wash U's Center for Genome Sciences, reported preliminary results of the study last week at the Cambridge Healthtech Institute's XGen Congress meeting in San Diego.

Fay and his team collaborated with Louis Muglia, associate director of the Vanderbilt Kennedy Center at Vanderbilt University, to sequence the mother of two pre-term children, who was born prematurely herself. They identified several SNPs that had previously been associated with reproduction problems, as well as novel SNPs that are also possibly associated with pre-term birth. They are now in the process of verifying those SNPs in other patients.

The study, while preliminary and mainly a proof of principle, demonstrates the apparent ability of whole-genome sequencing to identify potential causative mutations in complex, heritable diseases, said Fay.

Using a paired-end sequencing strategy on the Illumina platform, the team generated about 9 gigabases of aligned sequence, representing about a 3-fold coverage of the genome. The cost of reagents for the sequencing was around $16,000.

Fay's team called around 900,000 high-quality SNPs, 3,000 of which were non-synonymous. They then used an algorithm developed in-house, called the "likelihood ratio test," and predicted that 353 of those SNPs were deleterious.

Further analysis of those SNPs identified potential candidates that could affect preterm birth. Two SNPs had previously been identified as being involved in reproduction problems. One, which is present in 66 percent of the population, is associated with recurrent miscarriage and preterm birth. Another SNP, present in 41 percent of the population, is associated with second trimester pregnancy loss.

Additionally, the team found 130 SNPs that were not in dbSNP. Fay then looked at the genes that were associated with different aspects of reproduction and birth and found two of those novel SNPs located on genes important in uterine contractions. "A couple of rare mutations in the same pathway is encouraging that there might be something going on," said Fay.

Fay said his next step is to follow up on those initial results by resequencing the genes of interest in other affected patients. He said they have about 200 additional cases and 200 controls. Because of cost concerns, they are not doing whole-genome sequencing of those individuals, but are just resequencing candidate genes to see if any of the SNPs identified in the first patient are present in the others.

Recently, researchers have used whole-genome sequencing and exome sequencing to find causative genes in Mendelian diseases like Miller Syndrome and Charcot-Marie-Tooth Neuropathy (see In Sequence 3/16/2010). Also, there are several more projects, including one funded by National Heart Blood and Lung Institute, to use exome sequencing to identify causative genes in heart, blood, and lung diseases. Other studies include one jointly funded by the NHBLI and NHGRI that seeks to use exome sequencing to find genes involved in both Mendelian disease as well as more complex diseases such as Alzheimer's.

The finding of causative genes for Mendelian diseases has "generated considerable excitement in the field to identify mutations that underlie more common and also more complex diseases," said Fay. "For Mendelian disease, you can find the one causative gene, but you still need to sequence multiple individuals. We only had one," he added.

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