Another attempt to explain genetics

[Guest guest]

Here's another attempt to explain genetics, and the difference

between a simple genetic disorder (1 gene) and a complex genetic

disorder (3 genes).

Suppose that two parents both carry 1 copy each of a recessive/mutant

gene for a disease (such as cystic fibrosis), but have 1

dominant/normal copy of the gene. Both parents would be disease-free

because you need 2 copies of the recessive/mutant gene to develop

cystic fibrosis. The parents would be " carriers " . Using CFTR to

denote the normal or dominant gene, and cftr to denote the

recessive/mutant gene, the two parents would each be of genotype

CFTR/cftr.

Their children can randomly inherit one version of the gene from each

parent. So the two parents could have the following types of

children: CFTR/CFTR, CFTR/cftr, cftr/CFTR or cftr/cftr. Only the

cftr/cftr children (1 in 4, or 25%) would develop cystic fibrosis.

In this example, the prevalence of the disease amongst siblings would

be 25%, whereas the prevalence in the general population is 1 in

2,500 to 3,500 Caucasian newborns ( = 0.03 to 0.04%), so

the " heritability coefficient " would be about 700 (i.e. 25 divided by

0.035).

Consider now that to develop PSC one needed 3 different mutant genes.

Let's use A, B and C to denote the normal/dominant versions of the

genes, and a, b and c to denote the mutant/recessive versions of the

genes. Let's suppose that both parents were Aa, Bb, Cc. The children

could be any of these 64 possibilities:

AA, BB, CC

AA, BB, Cc

AA, BB, cC

AA, BB, cc

AA, Bb, CC

AA, Bb, Cc

AA, Bb, cC

AA, Bb, cc

AA, bB, CC

AA, bB, Cc

AA, bB, cC

AA, bB, cc

AA, bb, CC

AA, bb, Cc

AA, bb, cC

AA, bb, cc

Aa, BB, CC

Aa, BB, Cc

Aa, BB, cC

Aa, BB, cc

Aa, Bb, CC

Aa, Bb, Cc

Aa, Bb, cC

Aa, Bb, cc

Aa, bB, CC

Aa, bB, Cc

Aa, bB, cC

Aa, bB, cc

Aa, bb, CC

Aa, bb, Cc

Aa, bb, cC

Aa, bb, cc

aA, BB, CC

aA, BB, Cc

aA, BB, cC

aA, BB, cc

aA, Bb, CC

aA, Bb, Cc

aA, Bb, cC

aA, Bb, cc

aA, bB, CC

aA, bB, Cc

aA, bB, cC

aA, bB, cc

aA, bb, CC

aA, bb, Cc

aA, bb, cC

aA, bb, cc

aa, BB, CC

aa, BB, Cc

aa, BB, cC

aa, BB, cc

aa, Bb, CC

aa, Bb, Cc

aa, Bb, cC

aa, Bb, cc

aa, bB, CC

aa, bB, Cc

aa, bB, cC

aa, bB, cc

aa, bb, CC

aa, bb, Cc

aa, bb, cC

aa, bb, cc

Only the aa, bb, cc child (1 in 64 = 1.56%) would develop PSC.

Because the prevalence of the disease in the general population is

estimated to be 8 to 14 per 100,000 persons = 0.008% to 0.014%

the " heritability coefficient " would be about 100 if you use the

upper value of 0.014% (the " heritability coefficient " equals the

prevalence among siblings divided by the general population

prevalence). This is similar to the data described by Karlsen for PSC

(Karlsen TH, Schrumpf E, Boberg KM 2007 Genetic epidemiology of

primary sclerosing cholangitis. World J. Gastroenterol. 13: 5421-

5431).

So my guess would be that there may be 3 susceptibility genes

involved in PSC using this recessive gene model. Note that the

disease would appear to spring out of nowhere ... neither parent has

the disease.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)