How do the millions of genetic variants - ranging in size from a change in a single nucleotide (the As,Ts,Cs and Gs that define the genetic alphabet) to huge rearrangements of chromosomes that can affect many different genes - found in each human chromosome affect the health, longevity and lives of people? In a major report in the journal Science, an international consortium of groups that includes the Baylor College of Medicine Human Genome Sequencing Center describe an analytical approach applied in tens of millions of variants from 1092 humans that can be used to help answer that question.
Their work characterizing these rare variants and their presence in important regions of the genome helped identify biologically important areas that have significant effects both in the germline genomes (which can be inherited) and the somatic or tissue level genomes.
The study was made possible by several recent large-scale genomics projects, including the 1000 Genomes and the Cancer Genome Atlas projects, in which the BCM Human Genome Sequencing Center plays a major role.
"The critical lesson in a number of recent studies including this one is that when the number of genomes included in a study increases to a few thousands, we can better refine the frequency of different gene copies (alleles), particularly those that are rare," said Dr. Richard Gibbs, director of the BCM Human Genome Sequencing Center and the local principal investigator for this study. "This factor predominantly increases our discovery power for disease mutations and highlights the defining value of the large-scale sequencing efforts where a few of sequencing centers collaborate and take on major challenges like the 1000 Genomes and the TCGA."
The international collaboration not only generates data but also brings together bioinformatics expertise to tackle analytical challenges in a timely manner.
"Informatics is increasingly pivotal in biomedical research enterprise across the board. This is going to be a differential variable in the equation that dictates study design and scientific findings when we try to integrate biomedical big data to enhance the signal to noise ratio," said Dr. Fuli Yu, assistant professor in the BCM Human Genome Sequencing Center. His team consists of statisticians and computer scientists who are developing software tools and investigating properties of genetic variants.
Others from Baylor who took part in this work include Danny Challis; Uday S. Evan, and Donna Muzny.
Funding for this work came from the Danish Council for Independent Research Medical Sciences; the Wellcome Trust (Grants WT085532 andWT095908); the Wellcome Trust Sanger Institute (Grant 098051); the National Cancer Institute (Grants R01CA152057 and CA167824); the National Human Genome Research Institute (Grants HG005718, HG007000, R01HG4719 and U01HG6513); and the National Institute of General Medical Sciences Grant GM104424).
Gibbs also holds the Wofford Cain Chair in Molecular and Human Genetics at BCM.