ASU professor outlines importance of including sex chromosomes in genetic screenings
Genetic screening procedures identify genes that make an individual more at risk for certain diseases, improving doctors' ability to diagnose and treat their patients. A new study shows how to improve those screenings to include the sex chromosomes. Image courtesy of Cutler Integrative Medicine
If a doctor wants to assess a patient’s risk for getting a whole range of diseases, from cystic fibrosis to cancer, they have the incredible ability to do so by looking at the patient’s unique set of genes in a process called genetic screening.
But Melissa Wilson, an adjunct professor in the School of Life Sciences and a principal investigator with the National Institutes of Health, says that genetic screenings often overlook an important part of the human genome: the sex chromosomes.
“You can’t actually claim you’ve done genome-wide analysis if you haven’t included the X and Y,” Wilson said.
She and her colleagues recently published a study in the American Journal of Human Genetics that presented steps to better include the sex chromosomes in genetic screening, which they show can improve the accurate detection of mutations associated with diseases like Alzheimer’s, immunodeficiency and cancer.
In genetic screening, researchers use software to compare an individual’s genome to a reference genome in order to spot which of the individual’s genes are mutated. While most mutations aren’t harmful, some are associated with certain diseases.
That process of identifying harmful mutations works well for autosomes, or the non-sex chromosomes in the human body. Autosomes come in matching pairs with the same genes occurring around the same places on each chromosome, making it easy to consistently compare the autosomes to the reference genomes.
But sex chromosomes don’t always come in matching pairs. While females tend to have two X chromosomes, most males have an X and a Y chromosome that are very different from each other. There are also many other combinations, like males with XXY or females with only one X chromosome.
According to Wilson, researchers do not always take care to make sure they are using a reference genome that matches the sex chromosomes of the person they are screening. That means a researcher might compare an individual’s XX chromosomes to a reference genome with XY chromosomes (or vice versa). That can lead to classifying certain genes on the Y chromosome as having mutations when they actually do not, or missing some mutations entirely.
Wilson’s method works to both increase the number of mutations found and reduce the number of falsely identified mutations.
“We do two steps. One is making sure the reference genome is representative of the sex chromosome complement of the sample,” she said.
That means making sure that a researcher knows the chromosome combination of their patient, and taking care to use a reference genome with chromosomes that match to be able to identify all the mutations that are present.
Though it might seem obvious what a person’s sex chromosomes are based on whether they’re male or female, Wilson insists that “you can never know what a person’s sex chromosomes are just by looking at the person — you can make an educated guess, but you really can’t know without looking at the DNA.”
Once a researcher knows they are matching up a person’s chromosomes with a reference genome to maximize the number of mutations they are finding, they can take the second step: telling the software whether there is one copy of a chromosome (making it haploid) or two copies (diploid).
In autosomes, because the genetic screening software expects there to be two chromosomes, it looks to see whether there is a mutation at the same site on each matching chromosome, or looks for two variants. Without telling the software that there is only one chromosome, the software might say there is a mutation where there actually is not. That’s how haploid calling can eliminate those false identifications.
Haploid calling is an easy step to take, Wilson said.
“Most of this software have approaches built in to call variants as haploid on chromosomes with one copy. You just have to implement that step," she explained.
“But there are major consortium efforts that never bother to take the time to implement the haploid calling or thresholds because it’s easier (not to). So we tested how big of a difference does that make, and we reduced false positives by several-fold, and increased true-positive variant detection by tens of thousands of variants.”
Wilson and her colleagues provided evidence that following the steps they lay out can greatly improve the ability to find mutations on the sex chromosomes associated with certain diseases. Now, Wilson’s job is to make sure doctors and researchers actually follow those steps:
“There’s certainly a movement to include the whole genome. But still, I sit on calls with lots of people doing really incredible work, and I still have to be the one to ask, ‘Hey, are you including the X and Y?,’ And the answer is not always yes,” she said.
“It's kind of like the autosomes take a big step forward, and the X and the Y kind of tiptoe behind. I’m just here to like, hold their hand and make sure they catch up.”
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