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The genomic basis of medicine 

The genomic basis of medicine

Chapter:
The genomic basis of medicine
Author(s):

Paweł Stankiewicz

and James R. Lupski

DOI:
10.1093/med/9780199204854.003.40202
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date: 23 April 2017

During the last two decades it has become possible to determine the entire DNA content of living organisms—the genome. The completion of the human reference DNA sequence has provided an enormous amount of DNA sequence data and has extended our view of the genetic bases of disease.

Several structural variation studies (e.g. the HapMap and ENCODE projects) have revealed that human genetic variation is tremendous and consist of two major types: nucleotide sequence and genomic structural changes.

A first phase of the studies on genetic variation in humans has been focused on single nucleotide polymorphisms (SNPs). The large number of SNPs identified has enabled successful genome-wide association studies for disease risk of complex traits, e.g. diabetes and cancer.

Recent technology developments enabling a higher-resolution analysis of the human genome have uncovered extensive submicroscopic structural variation, copy-number variations (CNVs). CNVs involving dosage-sensitive genes result in several diseases and appear to contribute to human diversity and evolution.

An emerging group of genetic diseases have been described that result from DNA rearrangements rather than from single nucleotide changes. Such conditions have been referred to as genomic disorders.

Recurrent rearrangements, or those of common size and having clustered breakpoints, most frequently result from a mechanism of nonallelic homologous recombination (NAHR) between region-specific low-copy repeats, or segmental duplications. Nonrecurrent rearrangements, or those for which breakpoints do not cluster and that are generally different in size amongst families, can result from nonhomologous end-joining (NHEJ) recombination mechanism. Recently, a DNA replication mechanism has been shown to play an important role in the origin of nonrecurrent rearrangements.

The development of array-based comparative genomic hybridization (array CGH) has enabled high-resolution screening of genomic imbalances throughout the entire genome with the level of resolution depending only on the size and distance between the arrayed interrogating probes.

In the current postgenomic era both high-resolution genome analysis by array CGH and personalized diploid genomic sequencing applied to the study of inherited and complex traits promise a continued revolution in our understanding of normal physiology and the pathophysiology of disease heralding the genomic basis of medicine.

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