[Music] 

[The National Foundation, The March of Dimes presents] 

[Medical Genetics III, Genes in Families and in Populations]

[Music]

[Under the direction of Victor A. McCusick, William J. Young, Edmond A. Murphy]

[Music]

[Narrator:] In man, observations on the distribution of traits in families or kindreds, 

in so-called pedigree pattern, is the main method of genetic study. 

Since critical matings cannot be made by design, the human geneticist must rely on collections of families 

for information relating to Mendel's two laws, 

that of segregation, and that of independent assortment. 

The pedigree method may also provide information on the two related matters of allelism and linkage. 

Single-factor inheritance is studied by pedigree patterns. 

Study of a particular trait in a family usually begins with an affected person, 

who is referred to as the proband or the propositus, 

or sometimes as the index case and is indicated by an arrow in pedigree charts. 

Males are represented by squares and females by circles. 

Although the astrologic symbols are preferred by some. 

Marital lines are indicated thus, and double lines are used if the mating is consanguineous, as, for example, between first cousins. 

Usually persons with the trait in question are indicated by filled-in symbols. 

More-complicated devices can be used to indicate the presence of multiple traits 

or to indicate the several manifestations of a single syndrome. 

Traits and rare diseases of man are distributed in families in characteristic patterns, 

which are in accordance with Mendel's law of segregation. 

The specific pattern is dependent on whether the responsible gene is located on one of the autosomes, or on an X chromosome. 

It is also dependent on whether the gene in single dose, that is in the heterozygote state,

suffices to produce the phenotype under study. 

Or, whether the gene must be present in double dosage, or homozygous state for development of the trait. 

Traits observable in the heterozygous person are termed dominant,dominant. 

Whereas those which occur only in persons homozygous for the given gene are termed recessive. 

Autosomal dominant inheritance is illustrated by the kindred with brachydactyly studied by Farabee 

soon after the rediscovery of Mendelism.

The trait occurs in successive generations. And since it is a rare condition, only one parent has it. 

Among the offspring of a man or woman with brachydactyly, on the average, 

half the sons and half the daughters are affected. 

This result is expected when the responsible gene is located on one of a pair of autosomes. 

Since only one of each pair is contributed to a given offspring by the affected parent. 

The chromosome given to a child may, with equal likelihood be either the one bearing the mutant gene for brachydactyly, 

or the one bearing the normal or wild type gene. 

Classical achondroplastic dwarfism also behaves as an autosomal dominant trait. 

The family shown here is of particular interest 

because an achondroplastic woman bore three children, 

each by a different husband. 

Two of the three children were affected. 

Dominant traits tend to show rather wide variability. 

The degree of severity is referred to as the expression of the trait. 

When the expression is reduced to the point that persons with the gene 

cannot be distinguished from those without it, 

then the trait is said to be non-penetrant. 

Expression of a dominant trait as observed in a large series of cases is described by a bell-shaped curve. 

The largest number of cases have an intermediate grade of severity. 

Some are very severe, some very mild. 

These variations may be the effects of modifier genes. 

Environmental factors also influence the expression of gene action. 

Like dominant traits, autosomal recessive traits such as albinism, 

affect both males and females. 

Usually both parents are phenotypically normal, but both are carriers, that is heterozygous for the mutant gene in question. 

And by special tests may show mild abnormality. 

Since related individuals are more likely to be heterozygous for the same rare mutant gene, 

consanguineous matings are more likely to result in offspring affected by a recessive trait. 

The more rare the recessive trait, the higher is the proportion of parental matings, 

which are found to be consanguineous. 

For a rare condition, such as albinism, the proportion of parents who are first cousins may be as high as 10 percent,

and much higher consanguinity rates have been observed with even rarer traits. 

In the case of very rare recessive disorders, parental consanguinity may be the first clue

to its inherited nature. 

Among the offspring of two heterozygous parents, the risk of any one child's being homozygous and affected is one in four. 

The chance of being heterozygous is two in four, or one-half. 

And the chance of being free of the mutant gene is one in four. 

Shown here is the pedigree of an inbred kindred in which seven cases of the Crigler-Najjar syndrome 

have occurred in three related sib-ships. 

Jaundice is a leading feature of this syndrome, an inborn defect in the excretion of bilirubin. 

It is inherited as an autosomal recessive. 

In one section of this pedigree, studies showed that heterozygotes have a reduced ability 

to conjugate bilirubin. 

A second autosomal recessive disorder, the Morquio syndrome, also occurred in this kindred. 

If an individual affected by a recessive trait marries a homozygous normal person, 

none of the children will be affected., 

but all will be heterozygous carriers. 

If an individual affected by a recessive trait marries a heterozygote, 

then the expectation is that half the children will be affected. 

The pedigree pattern superficially resembles autosomal dominance. 

Previously there were thought to be two types of alkaptonuria, a more common form inherited as a recessive, 

and a rarer form, inherited as a dominant. 

This pedigree of alkaptonuria suggested autosomal dominant inheritance. 

However, on closer study, it was found that in at least two successive generations, affected persons married a relative. 

It is likely that the normal spouse was in each case a heterozygote, 

and the inheritance is indeed recessive. 

Dominance and recessiveness are of course attributes of the trait, not of the gene. 

As a matter of convenience, however, geneticist sometimes speak of a dominant gene or a recessive gene. 

Some traits are determined by genes carried on the x chromosome and are called sex-linked, 

or more precisely, x-linked. 

Such traits have the characteristic that transmission from father to son does not occur. 

This follows directly from the fact that the x chromosome in the male is transmitted to none of the sons, 

but is transmitted to every daughter. 

In females, x-linked traits may be either dominant or recessive, 

again depending on whether the phenotype is observable in the heterozygote 

or only in the homozygote. 

However, in males who, with only one x chromosome are homozygous, 

x-linked traits are regularly expressed. 

Rare x-linked recessive disorders occur almost exclusively in males, 

the condition, though not expressed in heterozygous females, is transmitted by them to half their sons. 

Among the children of an affected male, none of the sons is affected, 

but all the daughters are heterozygous carriers. 

If an affected male marries a heterozygous carrier, then a daughter may be homozygous and hence affected. 

Note that in such families, an affected male may also occur, 

but this is not an exception to the rule of no male-to-male transmission 

since the affected male inherited the trait through the mother. 

Hemophilia is the textbook example of an x-linked recessive trait. 

But pseudo-hypertrophic muscular dystrophy, 

colorblindness, and more than 50 other traits are known to be inherited in this manner. 

In the case of x-linked dominant traits such as Vitamin D-resistant rickets, 

heterozygous females are affected, as well as homozygous males. 

An affected female transmits the trait to half her sons and half her daughters 

just as for an autosomal dominant trait. 

However, an affected male transmits it to none of his sons, and to all of his daughters. 

Thus, rare x-linked dominant traits occur about twice as frequently in females as in males. 

The examples given up to now illustrate Mendel's first law, that of segregation. 

Characteristics such as the presence or absence of sickle hemoglobin are distributed in families, 

in accordance with the process of myopic segregation as outlined in the first film. 

The alternate genes which determine different forms of a given trait 

are called alleles and occupy identical positions, or loci, on homologous chromosomes. 

Genes at different loci are nonalleles. The distribution of traits in families may give information 

on whether particular genes are allelic or nonallelic. 

Alleles segregate. Non-alleles assort. 

Two examples are drawn from previous film. 

Are the genes for hemoglobin S and hemoglobin C allelic, 

that is, at the same genetic locus?

A tentative answer is provided by families in which one parent has both aberrant hemoglobins, 

and the other has only normal hemoglobin. 

In such families, it has been found that all children inherit either hemoglobin S or hemoglobin C. 

But to date, no child has inherited both, and none has inherited neither. 

Hemoglobin S and hemoglobin C are segregating traits. 

Their genes are by this criterion allelic. 

Are the genes for hemoglobin S and hemoglobin Hopkins 2 at the same locus, that is, allelic? 

Again, critical information is provided by families in which one parent has both of the aberrant hemoglobins 

and the other has neither. 

In this case, it is found that all four possibilities occur among the offspring. 

Some inherit both aberrant hemoglobins, some inherit neither, 

and others inherit one or the other. 

Here is illustrated Mendel's second law, of independent assortment. 

The genes for hemoglobin S and hemoglobin Hopkins 2 are non-allelic, 

are at different genetic loci, possibly even on different chromosomes. 

Non-alleles, assort. 

Chemical evidence also gives information on allelism and non allelism. 

In keeping with the current concept of one gene, one polypeptide chain, 

allelic genes determine variation in the same polypeptide chain., 

whereas non-allelic genes are concerned with different polypeptide chains. 

Even though in the same protein molecule. 

Thus, hemoglobin S and hemoglobin C are allelic and have changes 

in the beta polypeptide of hemoglobin A. 

Whereas hemoglobin Hopkins 2 is non-allelic with hemoglobin S and C, 

and has its change in the alpha chain. 

The chemical and genetic analyses lead to the same conclusion. 

Both allelism and non-allelism are demonstrated in this instructive pedigree of congenital deafness, or deaf-mutism, 

an autosomal recessive trait. 

In the first two generations, two deaf-mutes married, 

and in each case, all children were affected. 

In the third generation, again two deaf-mutes married. 

Each was affected by recessive congenital deafness, 

but all their children were normal. 

We can conclude that these parents were homozygous at different loci. 

This pedigree suggests the existence of at least two non-allelic genetic varieties of congenital deafness. 

Non-allelism can also be established by linkage studies. 

For example, in some families, elliptocytosis is determined by a gene at a locus close to the locus for Rh blood groups. 

In other families, elliptocytosis, which at present cannot be distinguished phenotypically, 

is determined by a gene at a locus not linked to that for Rh blood group. 

The genes for the two forms of x-linked hemophilia, classic hemophilia and Christmas disease, 

are non-allelic, where the gene for classic hemophilia is rather close to the colorblindness locus, 

whereas the gene for Christmas disease is located on the x chromosome at a greater distance 

from the colorblindness locus. 

Linkage is the occurrence of two loci on the same chromosome sufficiently close together 

that they do not assort independently. 

If two loci are on separate nonhomologous chromosomes, then independent assortment does occur. 

Even if two loci are on the same chromosome pair, they may be so far apart,

for example, one on the long arm and one on the short arm of a long chromosome, 

that independent assortment occurs through crossing over, 

just as though the loci were on separate chromosomes. 

Information on linkage is provided mainly by the offspring of a doubly heterozygous person 

and a person homozygous at the same two loci. 

But the gene in the double heterozygote may be either in coupling 

with the two dominants on one chromosome, 

and the recessives on the other,

or, in repulsion with a dominant and a recessive on each. 

In the two cases, the genetic distance between the loci is the same, 

but the phenotypes of the offspring who result from crossing over are different. 

Linkage is illustrated by the findings in 16 sib-ships reported in the literature, 

in which the two traits studied were Lutheran blood group and the secretor factor. 

The secretion or non-secretion of ABO blood-group substance into the saliva. 

In each of these families, one parent was doubly heterozygous 

and the other homozygous-recessive at both loci. 

The genotype of the parent homozygous recessive at both loci can be only the one shown here. 

However, the genotype of the doubly heterozygous parent can be either in coupling or in repulsion. 

In these data, note the strong tendency for children in a given family to be in either one class 

or the other. 

In those cases in which the doubly heterozygous parent was in coupling, 

the children were mainly of the types on the left side. 

When in repulsion, the children were mainly of the types on the right side. 

However, in each of seven families, there was at least one exceptional individual. 

For example, in family five, four of the five sibs are of expected types, 

but the fifth must be the result of a crossover in the doubly heterozygous parent. 

The same reasoning applies to the six other families where the indicated individuals are considered to be recombinants. 

The total number of offspring in each class is about equal, thus, no clue of linkage is provided. 

In all, 70 children occurred in these families. 

Of these, nine are recombinants and 61 are non-recombinants. 

Thus, the recombination fraction, chi, is nine out of 70, or 13 percent.

It is concluded that the Lutheran and secretor loci are on the same chromosome and about 13 map units apart. 

The lower the recombination fraction, the closer the two loci are on the chromosome. 

If the recombination fraction is 50 percent,

that is, if crossover and non-crossover progeny occur with equal frequency, 

then independent assortment obtains. 

The loci are either on separate chromosomes or far apart on the same chromosome. 

Linkage between markers and rare pathologic traits can also be investigated. 

However, the pathologic trait should be inherited as a dominant., 

for example, elliptocytosis, and must be identifiable in the great majority of persons heterozygous for the gene. 

In addition to the linkage of the Rh locus with that for one form of elliptocytosis, 

linkage has been demonstrated between the ABO blood group locus and the locus 

for the so-called nail-patella syndrome. 

The loci are thought to be about 10 map units apart. 

With the study of linkage with these rare diseases, it is necessary to use large kindreds, 

and all available data in each, since there are few of them. 

A method of choice in linkage analysis makes use of the principle of maximum likelihood. 

The chance of the constellation of findings in the family is computed for various values of chi, 

the recombination fraction. 

That value of chi which gives the greatest chance is the maximum likelihood estimate. 

In the time-consuming and error-fraught computations, 

the assistance of the digital computer is enlisted. 

It can provide points for curves such as this, derived from a group of families in which linkage of 

the nail-patella syndrome and the ABO blood groups was studied. 

Two important points. 

First, linkage is quite different from blood group and disease association. 

The association between blood group O and peptic ulcer has its basis 

in some physiologic peculiarity of the type O person, 

and not in the location of genes in the same chromosome. 

Indeed, linkage produces no permanent association of traits in the population. 

The second point, linkage must be distinguished from syndromal relationship. 

In the Marfan syndrome, dislocated lenses in the eye, long extremities and weakness 

of the aorta occur together. 

However, coincidences due, in this and most hereditary syndromes, to the fact that

one gene has widespread effects and not due to close linkage of several separate genes. 

Because of the recombination between homologous chromosomes 

through crossing over, even traits due to closely linked genes are found randomly combined after the passage 

of a number of generations. 

The objective of linkage studies is to map the chromosomes of man in as detailed a manner 

as has been achieved for drosophila and for the mouse. 

After two loci have been demonstrated on the same chromosome,

it still remains to be shown which autosome carries this particular linkage.

Cytogenetic approaches may help localize specific genes to specific chromosomes or parts of chromosomes. 

In the case of x-linked traits, linkage seeks to answer the question how far apart are two loci. 

The answer is provided by the proportion of recombinants among the sons of doubly heterozygous females. 

Here is a tentative map of the x chromosome showing the approximate relative position of the loci for xg blood group, 

glucose 6 phosphate dehydrogenase deficiency, colorblindness, hemophilia a, and others. 

The cornerstone of population genetics is the Hardy-Weinberg principle,

that the relative frequency of genotypes remains constant from one generation to the next, 

unless disturbed by factors such as mutation, selection, drift, and gene flow. 

It should be noted that whether a condition is inherited as a dominant 

has nothing to do with its frequency in the population. 

Consider a two-allele system which we will indicate as big A for the dominant gene, and little a for its recessive allele. 

The frequency of the alleles can be represented by p and q respectively, with p plus q equals one. 

The frequencies of the three genotypes possible with two alleles are p squared for big A, big A, 2pq for big A little a,

and q squared for little a, little a. 

Hardy and Weinberg directed thinking along lines of gene frequency 

as the pertinent variable in population genetics. 

If one collects from a population all cases of albinism, an autosomal recessive, and finds one case among each 10,000 persons,

this means a genotype frequency, q squared, of .0001. 

Q, the frequency of the gene little a, is the square root of this, or .01. 

The frequency of the dominant allele a is 1 minus .01 or .99. 

Note that the number of heterozygous carriers, big a, little a, can then be estimated. 

This value, 2pq, is 2 times .01, times .99, or about .02. 

One person in about 50 carries the gene for albinism. 

The relatively high frequency of carriers of recessive traits as compared with affected is demonstrated. 

Before considering the factors which disturb the Hardy Weinberg equilibrium, 

we should point out the problem of segregation analysis of rare recessive traits. 

One collects families that have at least one child affected by the trait. 

All of the affected persons are likely to have two normal parents, 

both of whom are, however, heterozygous for the recessive gene. 

Among the children of two heterozygous parents, one-fourth are affected. 

However, when all sibs in the ascertained families are added up, 

it is found that an appreciably higher proportion than 25 percent is affected. 

This is due to bias of ascertainment. 

Those parents who were both heterozygous, but who were fortunate enough to escape having an affected child, were not ascertained. 

Consider two-child families with both parents heterozygous for a rare recessive gene. 

In 16 such families, the first child will be affected in four, the second child will be affected also in four out of the 16. 

But, since this is an independent event, one expects that in only one family will both children be affected. 

When we undertake to collect such families in which both parents are heterozygotes for a rare recessive gene, 

we can usually recognize only those families which have at least one child who is affected. 

Of two-child families, only seven out of 16 can be ascertained. 

In six of the seven families ascertained, one child will be affected. 

In one of the seven, both will be affected. 

When we then assemble the 14 children from the seven ascertained families, 

we find that eight are affected, and six unaffected. 

Whereas the Mendelian expectation is that one-quarter of the offspring 

of two heterozygous parents will be homozygous and affected, 

we have found eight out of 14, or 57 percent, affected. 

If one can be sure that ascertainment is complete, 

a correction can be applied to test for agreement with the fundamental quarter ratio. 

If, as usually obtains, ascertainment is less than complete or uncertain, 

other or more complicated methods of analysis must be used. 

Factors which disturb the Hardy Weinberg equilibrium are drift, gene flow, mutation, selection. 

Genetic drift is a phenomenon which occurs in small populations. 

By chance, the gene frequencies in successive generations may deviate sharply from those 

in earlier generations. 

The smaller the population, the greater is the chance of large random shifts in gene frequencies. 

Genetic drift is nothing more than sample variance. 

Just as in experimental data, the variance is greater in studies involving smaller numbers of observations. 

Until as relatively recently as about 7000 years ago, when agriculture was developed on a wide scale, 

the human species consisted of small nomadic hunting groups. 

Genetic drift was probably a potent factor in changing the genetic constitution of man 

and accounting for geographic differences observed today. 

Gene flow results in changes in the genetic constitution of populations by adding new genes 

through migration, contact with invading armies and miscegenation. 

Gene flow from European to African peoples has occurred in the United States, 

through the period of over 300 years. 

Several genes occur in Africans south of the Sahara in relatively high frequency, 

but are rare or absent in Europeans. 

These include a particular Rh type, several other unusual blood groups, and a particular gamma globulin type. 

Estimates using these markers indicate that the present-day American negro has about 30 percent of his genes 

derived from European ancestors. 

Mutation occurring during gametogenesis in the parent generation 

will of course change, at least very slightly, the genotype frequencies in the offspring generation. 

Mutation is a relatively rare event, but nonetheless provides the raw material of evolution. 

It is the basis on which selection and the other factors discussed here mold the genetic constitution of the human species. 

Crude methods for estimating mutation rates in man are available. 

Although such estimates are subject to many inaccuracies, 

the rates which have been determined are of the same order of frequency as have been found in experimental forms. 

About 1 mutation per locus per 100,000 gametes. 

In other species, three classes of influences have been demonstrated to cause an increase in mutation rates. 

These are ionizing radiations, chemicals and heat. 

Presumably the same factors operate in man. 

Selection is a fourth factor which tends to disturb the Hardy Weinberg equilibrium. 

Fitness in the biological or Darwinian sense is defined in terms 

of the contribution made to the genes of the succeeding generation. 

Selection is differential fitness according to the genotype of the organism. 

Selection can operate on the haploid gamete. 

For example, in a heterozygous male, the sperms which carry one allele may be at a disadvantage 

as compared to those which carry the other. 

Furthermore, selection can operate on the diploid organism at any stage from that of the earliest zygote, 

to the time that the reproductive span is completed. 

The clearest example of the operation of a specific environmental factor in selection with regard to specific phenotypes, 

is provided by malaria and the sickle trait. 

The high frequency of the sickle gene in some populations, 

despite the loss of genes in the homozygous SS person with sickle cell anemia, 

suggests an advantage of the heterozygote. 

In these populations, sickling is a polymorphism as defined by Professor EB Ford. 

The occurrence together in the same habitat of two or more forms of a species 

in such proportions that the rarest of them cannot be maintained by recurrent mutation. 

Sickling is furthermore a balance polymorphism. 

In some populations, the frequency of the sickle gene is .40. 

This means that .4 squared, or 16 per 100 persons 

have sickle cell anemia, and die at a young age with loss of these genes. 

The frequency of the sickle gene would fall from 40 percent to a value below 5 percent 

in 18 generations if it were not for a balancing factor. 

Malaria in this population kills both AA and SA individuals early in life, 

but many more AA than SA individuals die. 

The result is that relatively speaking, more SA persons than AA persons survive to reproduce. 

At equilibrium, sickle genes lost in SS persons are balanced by the sickle genes saved by advantage of the SA persons. 

Evolution is change in the genetic constitution of the species. 

The factors which have been discussed as influencing gene frequency: mutation, selection, drift, 

and gene flow are the collaborating forces in evolution. 

The different genetic characteristics of the races which make up the one species, man, 

are the product of these evolutionary forces.

[Music]