Mate selection can amplify rare variants in children

Similar spouses: Partners who share related psychiatric traits also tend to carry similar amounts of rare genetic variants.

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Partners who share similar traits of a given condition, such as autism, may concentrate rare genetic variants in their children, increasing the likelihood of having a child with that condition, according to a new preprint.

Partner selection can put them beyond the point of no return for their offspring to develop the condition themselves, says John Constantino, a professor of psychiatry and pediatrics at Emory University in Atlanta, Georgia, who was not involved in the study.

The propensity of people to partner with others who share their traits, known as assorted mating, is thought to play a role in the heritability of psychiatric conditions. People with a psychiatric condition including autism, bipolar disorder, attention deficit/hyperactivity disorder and schizophrenia have a tendency to select a partner with the same condition, according to a 2016 study that analyzed medical records from the Swedish national registry of patients. These partner preferences could increase the prevalence of autism from one generation to the next, a follow-up study has suggested.

The new findings help explain the genetic factors behind these trends.

We’ve been hoping for that for a long time, says Constantino. Because when we saw these behavioral displays of mate selection, it was only a matter of time to get large enough and well-characterized samples to show that what we were behaviorally observing has the expected molecular and genetic underpinning.

TThe preprint looked at data on traits and genetic variants in more than 38,000 married couples from diverse datasets, including a population-based cohort called the UK Biobank and two North American autism cohorts: the Simons Simplex Collection and SPARK. (The latter two are funded by the Simons Foundation, Spectrums parent organization.) The work also collected data from a cohort of families carrying deletions in the 16p12.1 chromosomal region.

People with psychiatric traits are more likely than would be expected by chance to choose a partner with similar traits, the study found in all four cohorts, replicating previous findings. Within these couples, spouses have similar amounts of rare single nucleotide genetic variants.

Next, the study determined the genetic relatedness of the parents in the two autism cohorts by calculating the relatedness coefficients. The more genetically similar the parents are, the more likely their autistic children are to have long periods of homozygosity, in which the alleles inherited from each parent match, the researchers found. These runs have been associated with an increased likelihood of several neurodevelopmental conditions in other studies. This finding indicates that assorted mating could increase the likelihood of autism and other conditions in children.

mall variants that are most strongly linked to autism are de novo, meaning they occur spontaneously in the child and are not hereditary. But these variations can’t explain why autism tends to run in families.

Instead, some parents can pass on a type of mutation called a copy number variant, in which large portions of a chromosome are deleted or duplicated. The inherited copy number variant may not cause autism by itself, but it may make a child more vulnerable to the influence of additional genetic variants or mutations inherited from the other parent or de novo variants. This combination of variations is what can lead to autism.

It’s a combination of things coming together, and that combination is contributing to the phenotype, the severity you see in the baby, says Santhosh Girirajan, a professor of genomics at Pennsylvania State University at University Park and lead prepress researcher.

This multi-hit phenomenon was seen previously in another study of the 16p12.1 deletion: having the deletion alone increases the likelihood of autism, schizophrenia, and developmental delay, but having the deletion plus a second variant leads to a more severe phenotype . What determines what sets you on either of these trajectories is what successes you have other than cancellation, Girirajan says.

In the new work, Girirajan and his colleagues found that carriers of the deletion and their noncarrier partners have similar frequencies of psychiatric conditions, indicating nonrandom mating. For example, 20% of carrier partners have schizophrenia traits and 36% have symptoms of depression, while 12% of non-carrier partners have schizophrenia traits and 28% have symptoms of depression. Spouses also have burdens similar to rare variant.

When people with similar phenotypes and variable burdens have children together, genetic differences become more extreme over generations, with affected individuals having more affected children and unaffected or mildly affected individuals having more mildly affected children, the authors wrote. of the study in their preprint, which was published in medRxiv in May and has not yet been peer-reviewed.

The databases on which the study relied consisted mostly of people of European ancestry, which is a limitation, says Renato Polimanti, an associate professor of psychiatry at Yale University who was not involved in the study. Socioeconomic factors were also not taken into account and could play a role in the presence or absence of psychiatric traits as well as mate selection, he says.

Next, Girirajan and his team want to delve into how and why similar genetic variants can lead to different phenotypes, as well as the molecular changes that drive each trajectory.