GENETICS AND PUBLIC HFALTH

Medical practice has genetic effects of several kinds, By decreasing
the severity of hereditary disease, it allows the responsible genes to increase
in frequency, Through genetic counseling, 4t increases or decreases the
frequencies of some genes, Through diagnostic and therapeutic radiation,
and possibly some forms of chemotherapy, it induces mitations.

There is general agreenent among human geneticists that, in our present
state of comparative ignorance, genetic counseling shovld not be dominated
by consideration of long-term effects on the population. However, physicians
and other counselors should be familiar with the probable effects of in-
creased or relaxed selection against an hereditary disease,

In all cases, a stable equilibrium is reached when the number of genes
eliminated by death or reproductive failure equals the number arising by
mutation, For a rare dominant, this will happen when the frequency of the
disease equals twice the ratio of the mutation rate to the selective disad~
vantage (The factor of 2 enters because either homologous chromosom may carry
the mutant), Thus a disease dependent ona dominant gene with a mtation
rate of 1 per 100,000 genes per generation and a net fertility of 90 of
normal has a frequency’ 2(1079/-2) » or 2 per 10,000 persons, We see that:

1, If the mtation rate were permanently doubled, the disease
would become twice as frequent, approaching this equilibrium in a few genera=
tions. .

2, If the net fertility were increased to 95% of normal, the
disease would become twice as frequent. |

3, If the net fertility were reduced to zero by abstention from
reproduction, the frequency would be reduced to twice the mtation rate, or

2 per 100,000 persons.
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lh. The more harmful the gene, the less effective increased selection
would be, because a larger proportion of cases would be due to fresh mtavions,

A disease due to a rare sex-linked gene responds to altered selection
or mitation almost like a rare dominant, but the equilibrium frequency of the
disease in males is 3 times the ratio of the mutation rate to the selective
disadvantage, providing the mutation rate is the same in egg and sperms (The
factor of 3 enters because recessive sex~linked genes are exposed to elimination
only in males, which have 1/3 of the X chromosomes).

In the case of a rare, completely recessive autosomal gene, equilibrium
4s reached when the frequency of the disease equals the ratio of the mitation
rate to the selective disadvantage. If the frequency of the disease is
altered, return to the equilibrium frequency is very slow, because most of
_ the genes are protected in heterozygous carriers. Since the gene frequency
is approximately the square root of the disease frequency, only a very small
_ proportion of the genes in the population are due to fresh mutation, For exe
ample, with a mutation rate of 1 per 100,000 genes and complete lethality of
homozygotes, the disease frequency would be 1 per 100,000 persons and the
_ gene frequency 3 per thousand, which is 300 times greater than the mutation
rate, In the long run the same principles hold as for dominant genes, but
the immediate effects of increased mtation or altered selection on homozygotes
are very small, |

For an incompletely recessive gene, the equilibrium frequencies are
_ almost completely determined by the selection on the heterozygote, even if
‘this is very small. For example, if the lethal recessive gene considered
above reduced the fitness of the heterozygote by only 1%, the theory for a
dominant gene would apply and the gene frequency would be .O01, giving a
disease frequency of only 1 per million, If heterozygotes could be detected,
and would voluntarily reduce their fertility to 90% of normal, the frequency
of the recessive disease would be only 1 per 100,000,000 instead of 1 per

recessive

fe

100,000 as caleulated for the completely recessive gere. Thus
disease can be eliminated by a small reduction in fertility of heterozygous
carriers, |

Some physicians and geneticists have expressed concern about the ultimate
effects of relaxing selection against an hereditary disease, This concern
is based on the fact that at equilibrium the frequency of a dominant or re-
cessive disease is proportional to the ratio of the mutation rate, say u, to
the selective disadvantage, s. Therefore the total damage to the population
is the sum of (u/s)s, or simply the sum of the mutation rates, and we see that
the damage done by a deleterious gene is in the long run independent of how
deleterious the gene is, To put this another way, on the average every de-~
leterious gene leads to one genetic death, whether the disease it produces
is mild or severe, Therefore, unless each medical advance in the treatment
of hereditary disease is accompanied by some slight voluntary reduction
in the fertility of carriers, the ultimate effect will be an increasing de-
pendence of the population on medical care, with no reduction in the damage
due to genetic disease, Of course the severity of the disease in individual
cases would be reduced, but the number of people affected correspondingly
increased. .

These considerations no longer apply if the disease is completely cured,
However, an equilibrium will finally be established between opposing mutation
rates, and a large proportion of the population will require the necessary
therapy, as diabetics today require insulin or people with myopia require
glasses,

Most geneticists regard these prospects with some alarm and believe
that ultimately some voluntary reduction in the fertility of certain types
of genetic carriers should be encouraged, The above example shows that even
a very small fertility reduction is sufficient to lessen the present
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frequency of hereditary disease, even if great advances in medical care
normalize the survival of affected persons, There is general agreement
that it would be premature to encourage such changes in fertility mtil

human genetics has progressed farther,