Tuesday, May 27, 2008

genetics in general and particular

The life of Francis Crick was full and successful, he was involved in quite a few productive pairings, with James Watson, Sydney Brenner, Leslie Orgel, Christof Koch and others. He did some clever quite unbiological things during the war, and jumped late into biology, aged thirty-one. He discovered the double helical structure of DNA with Watson, and this opened up all sorts of questions about the genetic code. I only partly understand all this. The code contains degeneracy, junk in the genome as it was later called, but it took quite a while for them to realize this. Crick tended to be ahead of the pack, though, in intelligent guesswork. Take the adaptor. Crick wrote, for a small circle of leading geneticists who called themselves the RNA tie club, a paper entitled ‘on Degenerate Templates and the Adaptor Hypothesis’. His idea was that some combo of bases must provide information as to the choice of amino acids for particular locations. This was where adaptor molecules came in. He postulated 20 of them, one for each amino acid. Each adaptor would recognize some code which would bring in an amino acid to join a developing protein molecule. He didn’t speculate too much on the nature of this adaptor molecule, but it seemed likely to be a nucleic acid – that’s to say, RNA, which had become the next big focus for geneticists.

This was all quite theoretical, but the idea soon became empirically verified. Three labs discovered the process more or less simultaneously. Microsomes extracted from cells and placed in a test tube were shown to assemble proteins from amino acids. Before joining the protein molecule, the amino acids were attached to small RNA molecules, called transfer RNA. Many of those making these discoveries hadn’t realized that Crick had anticipated them in his speculations. Crick, on his side, was skeptical about the adaptor molecule being discovered, as he thought the transfer RNA was too big. Only as it became understood that each of the twenty kinds of amino acid had a specific transfer RNA molecule to do its job for it, did the fit between theory and evidence become clear.

My former step-daughter’s son has been diagnosed with a rare genetic disorder. It has taken some time for them to work it out, and now everyone’s undergoing genetic counseling, which is a new one for me. He has Trisomy 12q, which, according to this paper, is just coming to be recognized as a syndrome. It’s also I think called partial trisomy 12q, though every case seems to be different in its partiality. Jacob doesn’t appear to be trisomic for a large part of 12q – that’s to say he doesn’t generally appear too out of the ordinary. The child in this paper was described as dolichocephalic [long-headed]. Jacob has something of a large head, and I would tend to describe him as brachycephalic [broad headed], but these are possibly technical terms and I’m no expert.

The note given to me about Jacob was this – Trysomy 12q, sub tolomeric and monosomic 2p sub tolomeric. I presume this should read ‘telomeric’, and monosomic should read ‘monosomy’.

Telomeres are at the ends of chromosomes. They’re a popular focus of study in medical genetics as their shortening affects replication, which affects the ageing process and is implicated in cancers.

Trisomy is a form of aneuploidy, that’s to say, it’s a difference in the usual number of chromosomes, which can lead to abnormalities. Downes Syndrome is also known as trisomy 21, because there are three sets of chromosome 21 instead of the usual two.

Humans have 46 chromosomes in each cell, making twenty-three pairs. Chromosome 23 is the sex chromosome, with one x and one y chromosome for males and two x chromosomes for females. The complement of chromosomes of any eukaryotic species is called its karyotype. Normal human cells have 22 pairs of autosomal [non-sex – in which there’s no variation in the sexes of a species] chromosomes and one pair of sex chromosomes.

The most common form of aneuploidy, or aneusomy, is trisomy 21, which isn’t fatal. However, trisomy 18, known as Edwards syndrome, which is the next most common. occurs once in every 3000 live births, and is essentially fatal. Death occurs usually before term or shortly after birth [Or more likely most deaths occur before then but are undiagnosed].

According to this site, only trisomy 21, trisomy 18 and trisomy 13 [Patau’s Syndrome] cases, as cases of full trisomy, have made it to term. Some 95% of cases of trisomy are cases of full trisomy. This means that what Jacob has is, presumably, partial trisomy 12 q, and monosomy 12 p, though from what I’ve read, his case is mild compared to others. The site also states that full trisomies are not hereditary, though they are of course genetic. As to partial trisomies, I’m not sure.

I’ve received further info claiming that there seems to have been an attachment of chromosome 2 to chromosome 12, or something like that. Which perhaps explains why I read monosomy 2, and perhaps that’s right.

Is it worth trying to understand what partial trisomy 12 q is before looking at further complicating factors? What is a partial trisomy? I have assumed that Jacob’s trisomy is partial because only 13, 18 and 21 full trisomies have survived to term. However there is also mosaic trisomy.

Partial trisomy – the duplication of part of a chromosome rather than all of it.

Chromosomes have two parts or arms, joined by a centromere. These two arms are of unequal length, the short arm being labeled p, for petit, or petite, and the long arm being labeled q. However – and the penny has just dropped here – the reason Jacob’s condition was described as trisomy 12q and not partial trisomy 12q is because, presumably, all of the q arm of chromosome 12 has been duplicated, whereas if only part of that arm was duplicated it would be partial trisomy 12q. Any trisomy described with q or p is already partial.

Most commonly, the duplicated part of the chromosome attaches itself to another chromosome – and this apparently has happened to Jacob, the q arm of chromosome 12 attaching itself to chromosome 2.

I’ve discovered a site which gives a great intro to [partial] trisomies and their relation to [partial] monosomies, and how they come about, that is, through translocation [reciprocal in this case]. A balanced translocation in one of the parents has apparently led to an unbalanced translocation in the child. Where there’s an unbalanced translocation, you have more of one chromosome and less of another, so a partial trisomy will generally be accompanied by a partial monosomy, I think.

Groping towards an understanding…


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