B 1005; DEVIATION FROM MENDELIAN RATIOS (Two Lectures)

Mendel's Laws – generally, hold up well; genes are particles, assorting independently - as

manifest in the 9:3:3:1 ratio. Remind ourselves: simplicity – turns entirely on segregation

of independent particles, either two alleles at one locus or different loci. 2 x intro slides M

first law

Inevitably this beautiful simplicity has become confused in the light of modern genetics -

although the new information can be understood in the context in which Mendel himself

worked.

COMPLEXITIES OF DOMINANCE.

To Mendel - dominance a fundamental property of the gene; allows one allele to be hidden

by another, with no effect on the phenotype. However, now clear that dominance really an

attribute of the phenotype and not an absolute thing.

Many examples of incomplete dominance: heterozygote intermediate between the

dominant homozygotes. Four o'clock plant, Mirabilis japonica (named after fact that the

flowers open in the late afternoon). Normally red, but a white variety known. Cross Red

with White. All F1s are Pink - unlike either parent. Self these - get ratio: 1 Red: 2 Pink: 1

White.

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Easiest interpretation - no dominance - RW heterozygotes are intermediate between

parents; ie pink; ratio of 1 RR 2 RW 1 WW.

In fact can often see incomplete dominance underlying apparently normal dominance; eg

Mendel’s own peas: gene for round and wrinkled now found; in fact a starch-branching

enzyme which does not work properly, causing loss of water from cells and wrinkling of

pea. Heterozygote has intermediate starch molecules, although the phenotype looks the

same in both ww homozygotes and Ww heterozygotes.

In human genetics too; Sometimes – intermediate enzyme levels. Eg Tay-Sachs; nervous

degeneration disease – relatively common in Ashkenaze Jews; hets, known to be so

because have had children, have intermediate levels of hexosaminidase A enzyme; used

in counselling in old days; incomplete dominance.

Related – codominance; can see both phenotypes rather than an average of them.

Sometimes can see in visible characters – eg cross red and white cows – get patches of

red and white; ie both phenotypes visible. Interesting developmental biology question –

why are white alleles swiched on in some cells and red alleles in others? Now have some

idea, but complex.

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Codominance more or less universal at the molecular level. Eg disease sickle-cell

anaemia (substitution at one point in the haemoglobin chain); AA - healthy; AS - healthy:

SS - sickle cell disease. May be 100 million AS individuals in world; normally cannot be

distinguished. However - electrophoresis of haemoglobin (separate in gel with electric

field) allows AA, AS and SS to be distinguished. Codominance.

Counselling now revolutionised by ability to look directly at DNA; massive individual

variation to identify all those with just a single copy of a recessive allele; probes. Massive

differences at DNA level – dominance a property of the phenotype rather than the

genotype.

Multiple Alleles.

Mendel's peas - just two alleles at each locus - green or yellow, say. Now - cases with

many alleles: may be norm.

Sometimes - eg leaf patterns in clover - this is obvious, sometimes less so.

Drosophila eye colours in white eye series

Human eye colour variation – in fact very complex.

Good eg - ABO blood group system in humans. Agglutinated blood. Three alleles, A,

B and O; antigens O has none (just 4 sugars), A has an added n-acetyl galactosamine; B

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has an added galactose, AB has both those added sugars. Situation further complicated

by existence of both complete and incomplete dominance in the same system. Table

Blood Group Genotype

O OO
A AA or AO
B BB or BO
AB AB

Ie 3 alleles at this locus; one - 0 - the universal recessive: the other two - A and B -

codominant. Can give odd ratios.

Eg:

A 0

B AB BO

O AO OO

Ie an A parent and a B parent have children who are groups A,B,AB and O! Charlie

Chaplin taken to court in paternity case on blood group evidence; judge so confused that

he found him guilty and made him pay even though it was impossible that he had been.

Now - know even more alleles in this system: eg at least two sub-varieties of A.

Blood groups - a system of self-recognition based on cell surface antigens.

Histocompatibility antigens; discovered by Medawar at UCL - a far more diverse system of

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the same kind. Some loci - dozens, perhaps more, alleles: means that everyone is

unique. Important in tissue transplantation.

In fact, presence of multiple alleles now seen as more or

less universal at the molecular level for genetic disease

ie many different genetic accidents have caused the same

disease. Cystic fibrosis:over two thousand different

mutations are known. Some are common. One among them is

responsible for seventy percent of cases in Western

Europe. Two thousand miles to the East, that mutation is

in just a small proportion of patients. In some places (such as Jews in N Africa)

quite a different mutation causes the majority of cases. Great practical difficulty

for gene screeners – for cf, for example, can only tell someone that they DO carry

the disease, never that they DO NOT; for they might have a rare mutation which

the probe used does not recognise.

Lethal Alleles.

Early in genetics - odd ratio appeared. Yellow (light coat colour) mice.

Cross yellow with wild type - get ratio of one yellow to one wild type. Suggests that yellow

is dominant, and that the yellow parent was a heterozygote.

ie Yy x yy -> 1 Yy: 1yy.

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But - confusing result: mate two yellows together - get ratio of 2 yellows to one wildtype.

What is going on? If dissect pregnant mother in such a cross, find that there is another

class: but this dies very early. In fact one quarter of the embryos die in utero. The yellow

allele is lethal when it is homozygous. Cross is:

Y y

Y YY dies Yy yellow

y Yy yellow yy wildtype.

Notable that the pattern of dominance is different for two aspects of the phenotype. For

coat colour, Yellow is dominant: ie heterogyotes are yellow; For viability Y is recessive:

heterozygotes resemble the yy homozygotes as they are alive.

Many cases like this - eg Manx cats and many others.

In fact many of the classic "dominants" of human inheritance are like this. Some are not;

eg Huntingdon’s disease – if have two copies of the allele no worse off than if have only

one; but in many cases in fact we are dealing with a homozygous lethal. Eg Brachydactly

-in most pedigrees follows a classic dominant pattern of inheritance; every affected

individual has one affected parent; and about half the children of marriages between an

affected and a normal individual are affected. Very occasionally, though, two affecteds

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marry: and about one child in 4 dies soon after birth from severe skeletal damage.

Achondroplasia – ditto.

Pleiotropy - One Gene affects Many Characters.

Mendel - one gene, one character. Now realise that this is rarely the case: most genes

with a visible affect influence many characters simultaneously - pleiotropy.

Often unexpectedl Darwin – all blue eyed white cats are deaf! (to do with role of melanin

in ear). Many others – tabby cats: only ones found on farms, in general; largely because

have pleiotropic effect on behaviour; makes them more aggressive.

Classic case - effects of sickle cell substitution. At DNA and protein level as simple as can

be - change of one DNA base and one amino acid in the haemoglobin (Glu to Val in

position 6 of the beta chain). In homozygous state Causes change in molecule and

sickling of red blood cells; block blood vessels. Pleiotropic effects. Baby spleen

problem, brain, boss skull.

However, wide range of effects on phenotype:

Abnormal Hb

Sickling Clumping

Anaemia Tower

Weakness & Heart

Joint Accumulation Brain skull lassitude dilatation damage in Spleen

damage & kidney

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Heart Rheumatism Kidney Para- failure lysis

Ie wide range of symptoms from single substitution: plus another, unexpected, one: those

with a single copy of S (AS heterozygotes) are resistant to malaria as the parasite cannot

survive in the sickled cell - explains why gene is so common.

Some pleiotropy surprising and unexpected - eg Drosophila white eye has an effect on the

shape of the spermatogonia; but now we know that the white eye mutation is in fact of a

transport protein that fails to move the pigment to the eye and functions in many other

tissues too. Even found in human genome!

Classic example of human pleiotropy – single gene on the Y chromosome that makes

males male: produces simple chemical, testosterone – has, like sickle cell but much more

so, many different and at first sight unrelated effects. Particularly obvious in the wild – eg

male vs female peacock; human secondary sexual characters – moustache and baldness.

Testosterone

Secondary sexual characters – peacock

Human – moustaches

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Many genes are sex-limited; that is, they express themselves only in one sex. Must be

distinguished from sex-linked genes that are on the X chromosome but often deal with

things that have nothing to do with sex - eg colourblindness. Sex-limited genes can be

on any chromosome; often respond to sex hormones,

eg testosterone. Peacock tail. Male secondary sexual characters

Human analogy - sex-limited pattern baldness; all hair falls out at the age of c21.

Study pedigrees considering only males; follows classic autosomal dominant pattern.

However, no female ever shows the phenotype, although she can transmit the gene. Ie

the phenotype depends on the gene being placed in an environment in which there is a

lot of testosterone. Sometimes claimed that castration is a cure for baldness; but not

often used as a treatment!

Also the case that many (but not all) mental disorders are commoner in males than in

females; eg attention deficit hyperactivity disorder ADHD twice as common in boys as in

girls; schizophrenia commoner in men than in women although the genes scattered over

several chromosomes. In fact, many health issues – alcoholism eg, commoner in men

than in women; even gum disease commoner in men – obvious many are very indirect

effects (eg men brush their teeth less); but is a general result of a greater willingness to

take risks by males rather than females. And, of course, you may remember that I pointed

out in my lecture in the first week of the first term, men murder at ten times the rate of

women, whatever the local murder rate might be!

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This is a special case of pleiotropy: sex-limitation. Each sex has its own hormonal

milieu, which much alters the expression of a variety of genes and hence of

apparently unrelated characters.

Many genes are sex-limited; that is, they express themselves in different ways in each

sex. Have seen the baldness one, but others associated with female genotype - - those

for breast size, say. Some - very important. Breast cancer gene discovered; about

one case of this disease in twenty is familial; more or less Mendelian dominant pattern

of inheritance. Medical implications - eg talk of prophylactic mastectomy for young

women carrying the gene. Also treatment with drugs eg tamoxifen than block hormone

receptors, and you women at risk may take this from adolescence onwards to reduce

the risk. The gene nearly always shows its effects only in females (although there are a

few unfortunate males who carry the gene and develop breast cancer).

Next lecture – modifications of Mendel’s second law, independent assortment; although

his genetic ratio of 9331 may be correct, interaction between two loci can much modify

the phenotypes that can emerge.

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 KEY WORDS

MENDEL ONE
MENDEL ONE DOMINANCE
MIRABILIS INCOMPLETE DOMINANCE
EVEN MENDEL’S WRINKLED PEAS
TAY SACHS
HEXOAMINIDASE
WHITE RED CATTLE CODOMINANCE
ELECTROPHORESIS
SICKLE CELL
DNA VAR
MULTIPLE ALLELES CLOVER
EYECOLOUR DROS
HUMAN EYE COLOUR
ABO
CLUMPING
ABO RESULT
ABO CROSS
CF MULTIPLE ALLELES
YELLOW MICE
POSSIBLE BUT WRONG EXPLANATION
CORRECT – PRENATAL LETHALITY
MANX CAT
ACHONDROPLASIA
BLUE EYED WHITE CAT
TABBY AGGRESSIVE
SICKLE CELL
MUTATION
HB X 2

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SICKLING CELLS
PLEIOTROPY DIAGRAM
ENLARGED SPLEEN
BRAIN
HAND INFECTION
GENE INTERACTION – TESTOSTERONE
SEX LIMITATION PEACOCK
MALE SECONDARY – MOUSTACHE
BRCA 1 PROTEIN

INCIDENCE WITH GENE

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