About Family Trio Sequencing

Lab Note #3
Apr 18, 2015

This Lab Note provides some background about family trio sequencing, the technique that we will use in this project to search for genetic clues in autism.

A brief history

In 2008, the 1000 Genomes Project used family trio sequencing in a pilot study for quality control purposes. Ultimately, this multi-country effort produced a freely available database that maps human genome variation and continues to be an import resource for genomic research.

In 2010, researchers compared the exomes of two siblings with the same condition and found the genetic variant responsible for Miller syndrome, a single gene disorder. The exome is a kind of CliffsNotes version of the whole genome with recipes for building proteins. This technique has since been used to identify other genetic disorders.

More recently, researchers at Duke University used family trio sequencing to identify a rare disease involving a gene called NGLY1. In this New Yorker article, Seth Mnookin beautifully chronicles how the Might family searched for a diagnosis for their son, Bertrand.

How Family Trio Sequencing Works

In family trio sequencing, we search for differences in DNA between Mom, Dad and an affected child (called the proband). Technically speaking, we are looking for "accumulative" variants in the proband that include so called "double dose" or recessive variants, as well as genetic insertions/deletions (indels) and copy number variations (CNVs). We are also looking for "new" (or de novo) single nucleotide variants (SNVs) in the proband that are not seen in either parent. The diagram below shows how trio analysis separates the DNA sequence data into "new" and "accumulative" variants.

We will be using VarSeq software from GoldenHelix to quickly zero-in on genomic variants of interest. These variants will provide the genetic clues to autism.

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