(SALT LAKE CITY)—Scientists at the University of Utah (U of U), the University of Texas MD Anderson Cancer Center in Houston and colleagues have developed a powerful tool called pVAAST that combines linkage analysis with case control association to help researchers and clinicians identify disease-causing mutations in families faster and more precisely than ever before.
在一项关于 自然生物技术，研究人员 describe cases in which pVAAST (the pedigree Variant Annotation, 分析及检索工具) identified mutations in two families with separate diseases and a 新创 or new variation in a 12-year-old who was the only one in his family to suffer from a mysterious and life threatening intestinal problem.
"Linkage analysis and case control association traditionally have been used to find gene mutations,查德·赫夫说, Ph.D., 本研究通讯作者, assistant professor of epidemiology at the MD Anderson Cancer Center and former postdoctoral fellow in 人类遗传学 at the U of U. "Bringing those methods together provides a strong increase in the power to find gene variations that cause disease."
The advent of genome sequencing has allowed researchers to search for disease-causing mutations in the genomes of individual patients, larger groups of unrelated people or small and large families. The researchers in this study believe the most powerful way to identify these variants is by sequencing the genomes of families that experience unusually high occurrences of a particular illness. By identifying gene variations that family members share, it's possible to identify mutations in a gene that causes the disease, 根据 马克·杨德尔博士.D.的教授 人类遗传学 还是论文的资深作者.
"The issue with whole genome sequences has been that sequencing one person's genome to find a single disease-causing gene is difficult,杨德尔说. "If you can sequence the whole family it gives a fuller picture of the sequence and variations potentially involved in disease."
Humans carry two healthy copies of each gene in the body. But mutations in a gene can cause disease or other health problems. These mutations occur randomly and rarely, but once they happen in a family member, they are often passed down to subsequent generations.
pVAAST was designed to search the sequenced genomes of families to find shared mutations and thus identify the gene with the highest probability of causing disease. 不像其他基因发现工具, pVAAST accounts for people being related as it searches for gene variations that have the highest probabilities of causing disease. pVAAST的一大优势, 根据赫夫和杨德尔的说法, is its ability to simultaneously search multiple families with the same disease to find mutations; this reduces the amount of time and effort to find a disease-causing variant. 例如, if three families have the same disease, two might have different mutations damaging the same gene, while the third family might have a different damaged gene. "pVAAST has the power to determine the true disease-causing mutations across all those families in one analysis,杨德尔说.
相关工作, 扬德尔, 发怒, and their colleagues vastly improved the results of individual and small family sequencing by developing another gene-finding tool, Phevor (Phenotype Driven Variant Ontological Re-ranking tool), which combines the probabilities of mutations being involved with a disease with databases of phenotypes and information on gene functions. In doing this Phevor and pVAAST in combination can identify disease genes with much greater precision than other tools.
Sequencing genomes of unrelated patients with the same disease also increases the ability to find gene variations, and a third software tool 扬德尔 and colleagues developed, 变体注释, 分析及检索工具), has greatly advanced the speed and precision of doing that.
If VAAST or pVAAST can't identify the mutation most likely to cause a disease, Phevor can take the results from those tools and combine them with a description of the patients' disease called a ‘phenotype' to find the most likely causative gene.
“大发娱乐希望在开发pVAAST时, we and other researchers can more rapidly identify genetic variations influencing disease risk by increasing the statistical power of familial genome sequencing,哈夫说.
This study is a collaboration of several institutions in the United States and one in Europe. Lynn B. Jorde, Ph值.D., U of U professor and chair of 人类遗传学 and Martin Reese, Ph.D.他是加州奥克兰的首席执行官.总部位于美国的Omicia公司.，都是资深作者. Leroy Hood, m.s.D., Ph.D., of the Institute for Systems Biology in Seattle, is a co-author as is Stephen L. Guthery, M.D.的教授 pediatrics who referred a patient and his family for the study, 希拉里·库恩, Ph.D., research professor of psychiatry at the University of Utah School of Medicine.