Genomic approaches to the assessment of human spina bifida risk

Abstract

Structural birth defects are a leading cause of mortality and morbidity in children world-wide, affecting as much as 6% of all live births. Among these conditions, neural tube defects (NTDs), including spina bifida and anencephaly, arise from a combination of complex gene and environment interactions that are as yet poorly understood within human populations. Rapid advances in massively parallel DNA sequencing and bioinformatics allow for analyses of the entire genome beyond the 2% of the genomic sequence covering protein coding regions. Efforts to collect and analyze these large datasets hold promise for illuminating gene network variations and eventually epigenetic events that increase individual risk for failure to close the neural tube. In this review, we discuss current challenges for DNA genome sequence analysis of NTD affected populations, and compare experience in the field with other complex genetic disorders for which large datasets are accumulating. The ultimate goal of this research is to find strategies for optimizing conditions that promote healthy birth outcomes for individual couples. Birth Defects Research 109:120-128, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: biogeography; complex genetic disorders; intergenic (noncoding) sequence analysis; variant analysis; whole exome sequencing (WES); whole genome sequencing (WGS).

Figure 1. Rapid Growth of Genomic and Sequence Data

(A) The total number of whole genome sequences for humans has grown at an exponential or super-exponential rate in the past ten years, with an estimated nearly one million genomes to be completed by the end of 2016. (B) The size of sequence data in exabytes (right axis, red) and the total number of bases (left axis, blue) are also increasing at an exponential or super-exponential pace, indicating that a yottabyte of sequence data should be generated by the late 2020s. Exabyte (EB)=1×10¹⁸ bytes = a million terabytes; Yottabyte (YB)=1×10²⁴ bytes = a trillion terabytes