You have two copies of each chromosome, one from your mom and one from your dad. And your parents’ two copies get scrambled together before they get passed on to you, so the copy of chromosome 1 you got from your mom is a unique composite of the two copies she got from her two parents. Same with the copy of chromosome 1 you got from your dad.

This process is called recombination, and the mixing of genes it allows is one of the primary benefits of sexual reproduction. According to geneticists, anyway. But now it seems that recombination is responsible for more genetic issues than we had previously surmised.

Like elections and everything else in this world, recombination doesn’t always go smoothly, and different types of errors can happen. Genetic sequences can get inverted or duplicated when they are moved from one chromosome to another; or they can get spliced into the wrong place, disrupting a gene. These errors have clinical ramifications, often resulting in neurodevelopmental disorders, especially autism spectrum disorders and intellectual disability.

Chromosomal abnormalities are often still diagnosed by looking through a microscope at the actual chromosome (a process called karyotyping), despite the advent of sophisticated DNA tests. It is a powerful technique, but it is limited to changes that are big enough to disrupt the structure of a chromosome. If the cytogenic abnormality is small and balanced—if it occurs without any gross gain or loss of genetic material to the chromosome—it won’t be seen.

An international consortium of researchers mapped the sites of chromosomal abnormalities in 248 people with various congenital abnormalities, and their sequencing analysis revised the breakpoint identified by karyotyping in ninety-three percent of cases. This doesn't mean that karyotyping is wrong, just that it's very inexact compared to checking out the actual DNA.

Five percent exhibited a phenomenon known as chromothripsis or chromoplexy, which the authors define as “complex reorganization of the chromosomes involving extensive shattering and random ligation of fragments from one or more chromosomes.” In other words, the damage was patched up with some of the pieces and spare parts from elsewhere. (Not super relevant, but a cool concept to know about, right?)

Most of the breakpoints disrupted a gene, usually truncating it. Many of these genes had been previously implicated in developmental disorders. But disrupting genes is not the only way these abnormalities were found to cause pathology. Clusters of harmful chromosomal breakpoints were also localized to special regulatory regions that control the activity of the genes nearby. Disruption of these regions by these defects can thus affect an entire group of nearby genes and cause disease that way. This is not just hypothetical; the team demonstrated that changes in activity occur on at least four different chromosomes they examined.

Chromosomes are insanely long molecules, twisted and folded and torqued and looped around to fit into our cells. DNA sequences that are far apart when reading the molecule from one end to the other may thus be quite close together in 3D reality. Disrupting the complex architecture of chromosomes can cause disease by disrupting the physical interaction between a regulatory region and its target gene(s).

Balanced chromosomal abnormalities seem to do just that, and their import has not been recognized because the current means of diagnosing of chromosomal abnormalities cannot see them. The authors conclude by arguing for whole genome sequencing to detect these types of clinically meaningful abnormalities.

Nature Genetics, 2016. DOI: 10.1038/ng.3720 (About DOIs).