Was könnte eine kleine Maus lehrt uns über die menschliche angeborene Anomalien?

Mice are born with their eyes tightly shut, Öffnen sie zum ersten Mal nur ein paar Tage später. So when a mouse was noticed that was smaller than normal and had been born with it’s eyes open, sie lenkte die Aufmerksamkeit. Fehlbildungen wie diese entstehen spontan in allen tierischen Einrichtungen, but sometimes they are not one-offs, but inherited. It was not unexpected in this case, because the mother of this mouse was treated with X-rays to deliberately induce mutations, as part of a larger program of research aimed at producing animals that would be studied as models of human disease.

X-rays are the blunderbusses of genetic modification – almost no aim yet causing massive damage if they hit the target. Sometimes, they cause loss of whole chromosomes, oder bits of chromosome are lost and the cellular DNA repair machinery sticks the pieces back together. In the rare cases where the damage is not lethal either to the germ cell or very early in development, congenital abnormalities are seen in some of the live-born.

It turned out that our kleine Maus had lost a chunk of one chromosome, resulting in many Gene being present in only single copies, rather than the normal pairs.

There were two things we most wanted to know about our mouse – firstly, what other abnormalities did it have and secondly, how many (and which) Gene had been gelöscht? These gaps in our knowledge were important because if we could fill them, it would help us to understand the pathological effects of the deletion and be in a better position to compare mouse und menschlichen. It turned out that our mouse had a constellation of symptoms – altered head shape, a mild tail kink together with eyes open at birth and smallness. Furthermore, some painstaking developmental studies showed that many mice with the partially deleted chromosome died between mid- und full-term of gestation.

We first found this mouse back when whole genome sequencing was very expensive and financially impractical, so we relied on a combination of other, older methods to find out which Gene had been verloren. The simplest method uses a chemical stain that marks chromosomes with a characteristic pattern of bands, visible down the microscope (it’s shown in the picture at the top of this post), allowing an estimate of the percentage of the genome lost – this gave surprisingly close agreement with another method, based on genetic mapping, suggesting that 200-500 Gene waren verloren (we later worked out exactly how many – but that’s another story).

Despite the obvious differences, at the level of the genes, mice are a lot like Menschen – by chance, many of the genes deleted in our mouse have also been deleted in some humans. Furthermore, people with these partially gelöscht chromosomes have one of a number of complex congenital disorders or syndromes, depending upon which specific genes are lost. These deletions are fortunately rare, but some of the associated disorders are common e.g. hearing loss oder heart defects. Paradoxically, rare genetic events like this can teach us something about the other more common causes of these conditions.

Our small mice may be useful in studying why die Gene verloren in Menschen cause these specific abnormalities and even lead us to new therapies.

The work we did on this mouse was carried out at MRC Harwell and is described in detail hier.