Nature publishes largest database of human genetic variants to date

In this issue of nature, four related papers have been publishedIn addition, there are similar papers in the sub-issues of Nature Medicine and Nature CommunicationsIn today's article, the Academic Ethnos team will work with readers to learn about the gnomAD database, which is a milestone in human genetics researchthe advent of gene sequencing technology allows us to read all the genetic information of a person , the human genomeHowever, the greater challenge than measuring gene sequences is to understand the physiological function of these genesLittle is known about the function of most genes in the human genomeone wayreveal seditability of genes is to observe the results of genetic mutationsThese genetic variants, often inactivated by the proteins they encode, are called loss-of-function variantsBut such variants are rare in populations, which means that a very large genome sample size is required to discover the variant and assess the results of each variantThat's what large-scale databases are all aboutgenome aggregation database (gnomAD) project, data is pooled through a variety of large-scale population sequencing projects to identify various loss-of-functional variantsgnomAD project follows the publication in 2016 of ex-agnoson cluster symbiosis (ExAC), which contains data from more than 60,000 exon groups, mainly DNA fragments (exons) directly related to protein synthesis in the genomeAccording to an overview article in Nature, the new gnomAD not only brings together 125,748 whole exophotosequence sequences, but also contains 15,708 genome-wide sequencing data, increasing in size and scope, allowing more samples and more complex genetic variants to be systematically recorded and to understand variations beyond protein coding sequencesthe size and scope of gnomAD is larger and more esotathing to be interpreted (Image source: 5),the team screened a total of 443,769 predicted functional loss variants (predicted LoF, pLoF) variants from which the variation spree affected the normal functioning of their encoded proteinsThe researchers went on to classify the variants, from the ability to have little effect on physiological functions leading to serious health problems, in order to better identify the genes that cause common genetic and rare genetic diseases second article, the researchers focused on clinical interpretation of a particularly rare genetic variant Why should some genes not tolerate certain pLoF variants, but they can carry them with little effect? The researchers point out that when some genes are transcribed, the same gene forms different transcript isoforms due to differences in RNA shear, and that some exons have very limited levels of expression If a person has a pLoF mutation in a key gene in their body, the mutation is more likely to occur in an episotria with limited expression and therefore minimizes the effect but other transcription subtypes can lead to the emergence of specific diseases For example, a mutation in a gene that encodes the calcium channel can cause a rare disease called Timothy syndrome Different transcriptsubs of mutant genes are expressed in different tissues, resulting in multi-system disorders in patients to this end, researchers have developed a new indicator to quantify the transcription of genetic variants, creating a data set that could help in the genetic diagnosis of rare diseases and analyze the burden of rare variants in multisystem edgy diseases the third paper in the series explores how to identify candidate drug targets using a database of human functionally loss-making variants The researchers reported several key findings: First, genes that do not tolerate functionally loss-of-function variants (i.e essential genes) can still be viable targets for success to design the development of inhibitors Specifically, when it is found that some individuals carry two pLoF variants on a particular gene, this gene may be a good drug target Second, most of the functionally loss-of-the-type variants in most genes are very rare, and researchers have shown that there are many miscalculations when inferring such variants, so to collect definitive evidence, a queue 1000 times larger than the gnomAD sample size needs to be verified; In a fourth paper published Nature, researchers analyzed nearly 15,000 genome-wide sequencing data from the gnomAD database, creating a repository of structural variation structural variation (SV) refers to the rearrangement of large fragments of DNA on chromosomes, such as deletion, repetition, insertion, translocation, and even reversal of direction Such mutations are an important cause of many genetic diseases and cancers The researchers note that the rich library of 433,000 SV species "has a wide range of uses in population genetics, disease-related research, and diagnostic screening." a contemporaneous commentary in Nature noted that this large-scale genome sequencing and analysis effort produced the most comprehensive data and tools yet to understand genetic variation in humans GnomeAD has made these data and tools public This valuable genetic resource will change the way we interpret individual genomes, providing important information for us to understand the biological characteristics and diseases of humans, to assess rare and common genetic diseases References: 1, Konrad J Karczewski et al., (2020) the mutational call squantified spectrumed from the variation in 141,456 humans Nature https://doi.org/10.1038/s41586-020-2308-7 Nature https://doi.org/10.1038/s41586-020-2329-2 Nature https://doi.org/10.1038/s41586-020-2267-z Nature https://doi.org/10.1038/s41586-020-2287-8 S.S s.s s.s s.s s.s s.s smh.com.au smh.com.au smh.com.au Retrieved May 28, 2020, from https:// (original title: Important Milestones!) Today Nature publishes the largest database of human genetic variants to date)