Next generation sequencing and rare genetic variants: From human population studies to medical genetics

Abstract

The allelic frequency spectrum emerging from several Next Generation Sequencing (NGS) projects is revealing important details about evolutionary and demographic forces that shaped the human genome. Herein, we discuss some of the achievements of the use of low-frequency and rare variants from NGS studies. The majority of variants that affect protein-coding regions are recent and rare. Often, the novel rare variants are enriched for deleterious alleles and are population-specific, making them suitable for the study of disease susceptibility. To investigate this kind of variation and its effects in association studies, very large sample sizes will be necessary to achieve sufficient statistical power. Moreover, as these variants are typically population-specific, the replication of disease associations across populations could be very difficult due to population stratification. Therefore, the design of experiments focusing on the identification of rare variants and their effects should be carefully planned. Although several successes have already been achieved through NGS for genetic epidemiology, pharmacogenetic and clinical purposes, with improvements of the sequencing technology and decreased costs, further advances are expected in the near future.

Omics in population studies: A molecular epidemiology perspective

“…Among these technologies, the ones that have the potential to significantly improve our knowledge of diseases are certainly new sequencing techniques. The decrease of sequencing costs and the increased availability of instruments and technologies will bring the discovery of rare and private variants of many complex traits [Matullo et al, 2013]. The constant evolution of techniques creates new ethical dilemmas, such as incidental findings that can be easily generated by the management of the bulk information that can be retrieved from massive sequencing studies.…”

“…The constant evolution of techniques creates new ethical dilemmas, such as incidental findings that can be easily generated by the management of the bulk information that can be retrieved from massive sequencing studies. Research on ethics will play a growing role in the next few years, when personalized profiles of susceptibility to disease will be identified and their link to disease validated [Matullo et al, 2013;V€ ah€ akangas, 2013]. The main responsibility for the transfer of research tradition to the next generation of scientists through education-setting an example by their behavior-is in the hand of senior scientists, as well as in the ability of our universities to create qualified and easily accessible tools for learning molecular epidemiology [Arts and Weijenberg, 2013;V€ ah€ akangas, 2013].…”

Estudo da diversidade dos genes MC1R e SLC24A5 em populações globais: avaliação de aspectos evolutivos e ambientais

“…Diversas metodologias foram propostas neste contexto, incluindo, por exemplo, PCR em emulsão (454 -Roche, Ion Torrent -Life) e amplificação em fase sólida (SolexaIllumina) (Metzker, 2010;. (Matullo et al, 2013). Além dessas falhas, o método usado para inferência de genótipos e haplótipos não possibilitava a diferenciação de SNPs tri-alélicos, considerando-os bi-alélicos, reduzindo a informatividade de diversos loci .…”

“…As variantes de baixa frequência podem sofrer imputação com precisão de 60-90%, mesmo em populações miscigenadas (Genomes Project et al, 2012). Apesar de muitas melhoras terem sido alcançadas nas etapas de mapeamento, imputação e calling de genótipos, as tecnologias atuais ainda apresentam taxas de erros de, no mínimo, 10 -4 por nucleotídeo, levando a uma alta taxa de falsos positivos (em torno de 5%) quando a baixa cobertura é utilizada (Matullo et al, 2013).…”

“…As the sequencing costs decline, several collaborative projects for wholegenome sequencing have emerged, such as the 1000 Genomes Project (Genomes . Such projects, using distinct population samples, allow the discovery of new variants, elucidating important details about evolutionary and demographic aspects that shaped the human genome (Matullo et al, 2013).…”