Genomic Analysis in the Age of Human Genome Sequencing - Potluck 2/4/20

Tuuli Lappalainen, Alexandra J. Scott, Margot Brandt, and Ira M. Hall

March 21, 2019

The authors systematically explain the advances in genome sequencing over the years, highlighting the millions of whole human genomes we will soon have sequenced, while warning geneticists, clinicians, and the public that there are still many limitations to genome sequencing and its link to clinical efforts. While WGS studies are common, many iterations with high coverage must be done in order to separate mutations from sequencing errors. About 8.5% of the genome is difficult to sequence due to indels and high-copy repeats that easily cause misalignments and sequencing errors. This is important clinically since there have been multi-copy genes identified in these regions that have detrimental affects on individuals with mutations or varying amount of copies. A similar problem with sequencing structural variants (SVs) is noted, with a high percentage of sequencing error while accounting for 4-12% of high-impact coding alleles despite only making up 0.2% of total variants. High-read sequencing is still expensive and has a high error rate of up to 10% but there has been some promising progress towards methods that will increase the read length and decrease the cost as well as the error rate. The authors also warn against assumptions made about comparisons with the reference genome, stating that local ancestry estimates are more accurate for individuals whose genome sequence more closely matches the reference genome than those who do not. In the future, the authors hope that methodology will advance with functional annotation being able to identify developmental and environmental effects on cell type and regulatory elements. The authors state that we have made much progress in genome sequencing over the years but we still have a long way to go in making the methods cheaper, more widely used across the globe, error-free, and inclusive.

-Alexis Williams, Potluck 2/4/20

Link: https://doi.org/10.1016/j.cell.2019.02.032

https://www-sciencedirect-com.proxygw.wrlc.org/science/article/pii/S0092867419302156