Graduate Student, Harvard Medical School
Recommended by David Goldstein, Duke University
NEW YORK (GenomeWeb) – Kaitlin Samocha remembers filling out those Punnett squares in high school biology and getting excited about genetics. Of course, she quickly learned that those squares aren't used much outside the classroom as she took advantage of an outreach program at Washington University in St. Louis. While still in high school, she worked in a lab studying complex traits in a mouse model system, a theme she continued as an undergraduate.
But Samocha wanted to move beyond model organisms. "As fun as it was to really pin down some of these things in a mouse model organism, it was still a model organism, and I was interested in human traits," she told GenomeWeb.
In graduate school, she has focused on neurological and psychiatric disorders like autism and schizophrenia. These disorders, she noted are prevalent and not very well understood, though researchers are beginning to gain insight into their inner workings.
This change to human genetics meant, she noted, learning new computational and programming skills, which was challenging, but necessary so she could do her own analyses.
Samocha has also been working on constraint — determining what genes can tolerate genetic variants and what genes can't.
"That was almost a happy accident," she said. "It came out of some of the autism work we were doing."
While searching through exomes from child-parent trios for the source of the child's autism, she and her colleagues not only found de novo mutations linked to disease, but also realized they could identify rare variants in the population. They further found they could predict the number of rare variants they'd find in a population of healthy people. Some genes, though, appeared to be less tolerant of mutational changes than others.
These days, she is working on expanding that constraint work by using a dataset of some 60,000 exome sequences collected by Massachusetts General Hospital's Daniel MacArthur.
"We can use this information to take constraint and really refine it, so now we can look within regions of the gene versus the gene as a whole for a signal of constraint," she said, "and I think that's going to be more important in terms of prioritizing potential disease variants."
Paper of note
This past August, Samocha had a paper in Nature Genetics detailing a framework she developed to tease out the signals from de novo mutations from background mutations. She and her colleagues applied this approach to sift through exome sequencing data from 1,078 trios in which the child had autism and the parents did not.
From this, they found that there isn't an excess of de novo missense mutations in autism, but that there were more genes with multiple de novo missense mutations than expected.
This is also, she noted, how they came across constrained genes — which she and her colleagues said overlapped with their list of autism-related genes with de novo loss-of-function mutations.
Looking ahead
To understand complex diseases like autism and schizophrenia, Samocha said, researchers would have to begin combining data, such as protein expression level data, microbiome data, and more.
"I think that now we need to be able to take what we're finding from genetics and start to link it up with some of these other systems to really get a clear picture of what's going on," she said.
For example, she noted that genome-wide association studies have been able to connect hundreds of sites around the genome to disease, but researchers need to see how variants at those sites affect pathways and tissues to actually lead to disease.
"As much as I like finding the genes, finding puzzle pieces … you have to map them together at some point to see the whole picture," Samocha added.
And the Nobel goes to…
If Samocha were to win the Nobel Prize, she'd like it to be for elucidating the underlying biological basis of disorders like autism and schizophrenia.
"If we could really get to why these few changes in a few places can push you toward autism, I think that would be incredibly important to the field and to medicine and to all these patients," she said.
This is the eleventh in a series of Young Investigator Profiles for 2015 that will appear on GenomeWeb over the next few months.