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Protein Size Issues | The Scientist Magazine®

OOne of the lesser-known differences between people is that some individuals have larger or smaller proteins than others. This is because the genes encoding these proteins have repeating regions of DNA that can occur different times. Each iteration then adds an extra string of amino acids to the protein.

The most comprehensive analysis of these genetic stutters to date, called variable number tandem repeats (VNTRs), has shown a strong influence on traits such as height and baldness.Survey results released today (September 23) Chemistry, May help explain some of what is known as lack of heritability: known genetic variation in humans explains much of heritability in diseases, behaviors, and other phenotypes. I can not do it.

“If you have a short version of the gene, your protein may contain 1000 amino acids, and if you have a long version of this gene, you may have 2000,” said the Cambridge Broad Institute. Geneticist Ronen Mukamel said. , Massachusetts, and co-author of the study. “Literally, a protein grows or shrinks depending on whether its gene is large or small. It depends on whether its repeating elements are long or short.”

Geneticists have known for years the potential effects of VNTR, but these regions are more difficult to analyze directly than the causes of simple genetic variation such as single nucleotide polymorphisms (SNPs). is. One reason is that high-throughput genome sequencing techniques typically break down DNA strands into smaller pieces and then stitch together the sequences. Iterative elements like VNTR confuse this assembly process.

To avoid this problem, Mukamel and his colleagues used statistical techniques to indirectly estimate the size of the VNTR from existing DNA sequences and SNP data.

Keeley Brooks, a geneticist at Nottingham Trent University in the United Kingdom who was not involved in the project, says this is a good way to move forward. The lack of high-throughput technology that can detect VNTRs has hindered VNTR research, she says. Genome scale. ”

Mukamel and his colleagues used their technology to analyze the effects of VNTR on 118 protein-coding genes in more than 400,000 participants in the UK Biobank project, a database containing detailed genetic and health information. bottom. Next, we checked the association between these VNTR lengths and the 786 different phenotypes.

“For a small number of genes, we found that the size of the protein controlled by one of these repeating regions of the genome is strongly associated with the human phenotype,” says Mukamel. In some cases, he says, the effects of VNTR were greater than other known gene mutations.

Overall, researchers found a strong association between 19 phenotypes and 5 different VNTRs. Health-related features that may be affected by VNTR are associated with renal function, including elevated levels of lipoprotein (a), a major risk factor for coronary artery disease, and elevated levels of gout and serum urea. It contains several characteristics.

Height was one of the clearest signals.Changes in VNTR length within a gene ACANThe study showed that encoding the protein aggrecan was associated with a mean height difference between people of 3.2 cm. The longer VNTR found in this study is more than twice the size of the aggrecan domain, which has been known from previous studies to allow chemical modifications that help the extracellular matrix retain water. increase. However, researchers say it’s not clear how this change in water retention capacity affects height.

Bjarni Halldorsson, Icelandic deCODE geneticist, Studies published earlier this year We used another technique called long-read sequencing to identify the significant effects of VNTR on genes such as: ACAN About phenotypes including height. Such findings have the potential to expand the range of genetic tests available, he says. It seeks to assess the likelihood that someone will develop clinical and non-clinical features, including height. “There are already these companies undergoing these genetic tests. They probably haven’t tested this variant, but in theory it’s not difficult.”

Mukamel says the ability to detect VNTR length is already useful in clinics because it can be used to stratify patients enrolled in clinical trials due to the genetic risk of high lipoproteins (a). ).

Protein Size Issues | The Scientist Magazine® Protein Size Issues | The Scientist Magazine®

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