Fri. Mar 31st, 2023
Major genetic defects are often identified by looking for oddities in the chromosome pairs.
Enlarge / Major genetic defects are often identified by looking for oddities in the chromosome pairs.

You have two copies of each chromosome, one from your mother and one from your father. And the two copies from your parents get mixed up before being passed on to you, so the copy of chromosome 1 you got from your mother is a unique composite of the two copies she got from her two parents. The same goes for the copy of chromosome 1 that you received from your father.

This process is called recombination, and the mixing of genes it makes possible is one of the main benefits of sexual reproduction. At least according to geneticists. But now it seems that recombination is responsible for more genetic problems than we previously suspected.

Like elections and everything else in this world, recombination doesn’t always run smoothly and various types of errors can occur. Genetic sequences can be reversed or duplicated when moved from one chromosome to another; or they can be spliced ​​in the wrong place, disrupting a gene. These errors have clinical consequences, often resulting in neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disabilities.

Chromosomal abnormalities are often still diagnosed by looking at the actual chromosome through a microscope (a process called karyotyping), despite the advent of sophisticated DNA testing. It is a powerful technique, but is limited to changes large 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 on the chromosome – it will not be seen.

An international consortium of researchers mapped the sites of chromosomal abnormalities in 248 people with various congenital anomalies, and their sequence analysis revised the breakpoint identified by karyotyping in ninety-three percent of cases. This does not mean that karyotyping is wrong, just that it is very imprecise compared to checking the actual DNA.

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

Most breakpoints have a gene disrupted, usually truncated. Many of these genes have previously been implicated in developmental disorders. But gene disruption isn’t the only way these abnormalities caused pathology. Clusters of deleterious chromosomal breakpoints were also located in special regulatory regions that control the activity of the genes nearby. Thus, disruption of these regions by these defects can affect a whole group of nearby genes and thus cause disease. This is not just hypothetical; the team showed that changes in activity occur on at least four different chromosomes they examined.

Chromosomes are insanely long molecules, twisted and folded and twisted and looped to fit into our cells. Thus, DNA sequences that are far apart when reading the molecule from one end to the other can be quite close 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 appear to do just that, and their importance has gone unrecognized because current diagnostic methods for chromosomal abnormalities cannot see them. The authors conclude by advocating whole genome sequencing to detect these types of clinically relevant abnormalities.

Natural genetics2016. DOI: 10.1038/ng.3720 (About DOIs).

By akfire1

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