Variation in individual Genomes
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P56-57
2025-11-30
23
The most extensive current inventory of the amount and type of variation in any given genome, relative to the (composite) human reference genome sequence, comes from the analysis of individual dip loid human genome sequences. The first such sequence, that of a male individual, was reported in 2007. Now, hundreds of thousands of individual genomes have been sequenced, some as part of large international research consortia exploring human genetic diversity in health and disease, and others in the context of clinical sequencing to determine the underlying basis of disorders in particular patients.
What degree of genome variation does one detect in such studies? Individual human genomes typically carry ~3.5 million SNVs when compared to the reference genome, of which— depending in part on the population— currently 1% are novel (i.e., not previously documented). This suggests that the number of SNVs described for our species is still incomplete, although presumably the novel fraction will decrease as more genomes from more populations are sequenced.
Within this variation lie variants with clinical impact that are either known, likely, or suspected. Each genome carries 50 to 100 variants that have previously been implicated in known inherited conditions. In addition, each genome carries thousands of nonsynonymous SNVs in protein- coding genes, some of which would be predicted to alter protein function. Each genome also carries ~200 to 500 likely loss- of- function variants, some of which are present at both alleles of a gene in that individual. Within the clinical setting, this realization has important implications for the interpretation of genome sequence data from patients, particularly when trying to predict the impact of variants in genes of currently unknown function.
An interesting and unanticipated aspect of individual genome sequencing is that each new genome reveals some sequence that is still undocumented or unannotated in the reference human genome assembly. It is estimated that, once fully elucidated, the complete genome sequence representing the current world population will be 20 to 40 Mb larger than the extant reference assembly. Recently WGS performed on only 94 individuals from 44 African populations revealed 33.6 million SNVs, of which 5.7 million (17%) were novel. This illustrates the extent to which individuals of descent other than European are underrepresented among sequenced cohorts, creating a significant gap in our knowledge of human genetic diversity and our ability to advance genomic medicine.
Clinical Sequencing Studies
In the context of genomic medicine, a key question is the extent to which variation in the sequence and/ or expression of one’s genome influences the likelihood of disease onset, determines the natural history of disease, and/ or provides clues relevant to its management. As just discussed, constitutional genomic variants can have a number of different direct or indirect effects on gene function.
Sequencing of entire genomes (WGS, also referred to as genome sequencing) or of the subset comprising all known coding exons (exome sequencing) has been introduced in a number of clinical settings. Both exome sequencing and WGS have been used to detect de novo changes (both SNVs and CNVs) in a variety of conditions of complex and/ or unknown etiology. These include, for example, various neurodevelopmental or neuropsychiatric conditions, such as autism, schizophrenia, epilepsy, intellectual disability, and develop mental delay.
Clinical sequencing studies can target either germline or somatic variants. In cancer, especially, various strategies have been used to search for somatic variants in tumor tissue to identify genes potentially relevant to cancer progression.
Direct- to- Consumer Genomics
Access to laboratory genomic testing has moved into the public realm in recent years, no longer with mainstream medicine as its gatekeeper. Tests are marketed directly to consumers for information ranging from genealogy and ancestry tracing to information about personal health and inherited traits. Targeted screening panels are starting to give way to genome sequencing opportunities. A limited number of specific diagnostic tests have been authorized by the US Food and Drug Administration for marketing. There is considerable public appetite for the sort of individual information being offered commercially, and the massive volume of data being collected and stored has enormous research potential. Notwithstanding or minimizing the significant scientific, ethical, and clinical issues that lie ahead, it is certain that individual genome sequences will be an ongoing active part of medical practice and that some of these will be delivered from patient to practitioner, rather than vice versa.
الاكثر قراءة في مواضيع عامة في الاحياء الجزيئي
اخر الاخبار
اخبار العتبة العباسية المقدسة
