A DNA discovery that changed genomic medicine
In 2004, Dr. Stephen Scherer made a discovery: copy number variations in the DNA of genes were vastly more common than previously thought. In so doing, he transformed our understanding of the human genome, opening entirely new avenues for genetics research.
The Scientist
Dr. Stephen Scherer is a global leader in genomic medicine and one of the most highly cited scientists in the field of autism spectrum disorder, holding patents across 13 areas of science. The native of Windsor, Ontario officially joined SickKids in 1997 as Scientist after earning a Ph.D. in Molecular and Medical Genetics under world-renown supervisor Dr. Lap-Chee Tsui.
He has received a long list of recognitions over his career while maintaining his proud advocacy for Canadian science and positioning the country as a leader in genomics and precision medicine. Chief of Research at SickKids since 2021, Scherer is Senior Scientist, Genetics & Genome Biology and Director of The Centre for Applied Genomics (TCAG) at SickKids as well as Director of the McLaughlin Centre at the University of Toronto.
His research focus, through which he's co-authored >740 publications (h index=173), seeks to understand the composition of the human genome for studies of genetic disease in three themes: 1) Gene copy number and structural variation in the human genome; 2) Determining the genetic architecture in autism spectrum and related- disorders and using this information to help families; and 3) Developing infrastructure and capacity in Canada for translational genomics research.
The Discovery
Data from the Human Genome Project had shown that DNA inside the genomes of any two people were 99.9 per cent identical — that just 0.1 per cent variation arose from single nucleotide changes among the chromosomes. In short: such "copy number variants" (CNVs) were extremely rare.
CNVs are deletions, additions or reorganized parts of DNA and were generally linked to genetic disorders. But Scherer used novel genome scanning technologies to discover an initial 255 regions where long chunks of DNA were present in different copy numbers between healthy individuals. They found that these large-scale CNVs frequently overlapped with genes and, thus, could help explain someone's unique physical or behavioural traits. The CNVs also proved to overlap with regions associated with disease, influencing a person's future risk of genetic disorders.
Scherer and his team were stunned by this revelation, which upended what was known about DNA variations. He learned that researchers at Brigham and Women’s Hospital (led by Dr. Charles Lee) had made similar observations, and the two groups decided to pool their data for definitive proof of the finding.
They published this co-discovery in Nature Genetics in 2004, demonstrating to the world that CNVs are commonplace, not rare, and present in the genomes of all cells in every person.
The Impact
The initial breakthrough has transformed the scientific and medical communities’ understanding of our human genetic makeup and catalyzed a new field of genetic research.
Their revelation has had a major downstream impact on the diagnosis and treatment of many human disorders, including Scherer’s own work using CNVs to find genes that increase the risk of autism spectrum disorder. In testament, CNV microarrays are now recommended as standard-of-care for autism diagnostic testing in North America and Europe.
In ensuing years, Scherer:
- Founded the Database of Genomic Variants: This public database is a worldwide resource to interpret CNV data and is used in all major international genome databases. Today, it facilitates thousands of clinical diagnoses every day.
- Built CNV maps of human DNA: Scherer and collaborators revealed the structural properties, mechanisms of formation, and population genetics of CNVs, finding that they number in the thousands in every genome and contributing to the first whole genome sequence of an individual.
- Advanced field of diagnostics in autism: Alongside collaborators, Scherer has discovered many CNVs linked to disease including susceptibility genes in ~10% of people with autism. This led to new tests that are used globally as early diagnostic methods, including an evaluation system Scherer developed as a resource to assist in diagnostic testing.
- Championed open science: Scherer has long been a proponent of collaboration and open science, founding or leading major global resources and initiatives including TCAG, the Database of Genomic Variants, the Autism Speaks MSSNG Project and, more recently, PCHSeq, comprehensive sequencing for childhood life-long disorders that aims to conrtibute to Canada’s largest-ever collection of human genomic data, the Canadian Precision Health Initiative.
- Understanding autism’s genetic makeup: Through the MSSNG project, Scherer used whole genome sequencing to uncover key genetic contributors to autism, identifying >100 associated genes and variants. This provided answers for 20% of impacted families while revealing new therapeutic pathways and defining the genomic architecture of autism.