Genetics

To understand population genetics and evolution,we’ll begin with a brief review of Mendeliangenetics (Chapter 9)

The basis of modern trait genetics is Mendel’s studies.Mendel studied the garden pea - why?

Cheap, quick, basic traits well-knownMore importantly, only two phenotypes for each trait - flowers either purple or white, seeds either yellow or green,…

He was also ‘lucky’ - each is a single gene trait

each of the 7 traits he studied show simple dominance - a dominant gene, when present is always expressed in the phenotype

each shows complete penetrance - there are no washed-out colors or incomplete expression

when he studied multi-trait phenotypes, the pairs of traits he chose didn’t show effects of crossing over

What did he find?

In a cross for seed colour - yellow is dominant over green -

As long as you consider single factor crosses withsimple dominance, there are only a few possibilities:

both parents homozygous

YY Y Y

y Yy Yyyy y Yy Yy

all offspring will be identical

one parent homozygous, one heterozygous

YY 1/2Y 1/2Y

1/2Y 1/4YY 1/4YYYy 1/2y 1/4Yy 1/4Yy

offspring are half homozygous (like the homozygous parent) and half heterozygous

What’s important is to remember that half the gametes carry one of the parental chromosomes, and the other half carry the other parental chromosome.

both parents heterozygous

Yy ½Y ½y

½Y ¼YY ¼YyYy

½y ¼Yy ¼yy

1/4 of offspring homozygous dominant1/2 of offspring heterozygous1/4 of offspring homozygous recessive

Mendel found that a trait (e.g. green pea colour)could disappear for a generation (hidden as arecessive gene in heterozygotes), then reappearin the next generation. He invented the termsdominant and recessive. He proved it using a testcross (a cross with a homozygous recessive individual.

There are only two possible results: all offspring identical - unknown parent homozygous 1/2 and 1/2 - unknown parent heterozygous

The results of single factor crosses led to Mendel’sFirst Law - The Law of Segregation:

Each sexually reproducing organism has two allelesfor each trait. These alleles separate (segregate)during meiosis. Only one appears in each gamete.

Now consider two factor (trait) crosses -pea colour (yellow or green) and…pea shape (round or wrinkled) together

Results of a two factor cross of heterozygotes:

9/16 dominant phenotype for both traits 3/16 dominant for one trait, recessive for the other 3/16 dominant for other trait, recessive for first one 1/16 recessive for both traits

From results of two factor crosses, Mendel formulated the Law of Independent Assortment -

If traits are not located on the same chromosome, thenthey are distributed independently in the formation ofgametes.

Now let’s consider some human traits that areinherited simply, like Mendel’s traits in peas:

Mid-digital hair - presence (or absence) of any hair on any finger between the middle and distal joints I think this is a recessive.

Tongue -rolling - ability to curl your tongue into a U shape. An autosomal dominant.

Clockwise rotation of the whorl of hair at the top back of your head. Also autosomal dominant.

Brachydactyly - short fingers. An autosomal dominant.

Autosomal recessive genes?

Blue eyes - presence of pigment in the iris is dominant.

There are many others. We may be able todetermine whether a trait is dominant or recessivefrom a pedigree.

e.g.

Your assignment (not one that will be graded):

For the following single gene traits in humans,determine the phenotypes of your parents, siblings,and, if possible, your grandparents:

tongue-rollinghair whorlmid-digital hairHitchhiker’s thumb

We could try to determine your genotype for these traits from those of your relatives.

We use pedigrees to try to determine your genotypeor to determine whether a trait is dominant orrecessive.

Here’s a pedigree for an autosomal dominant trait:

And here’s a pedigree for a recessive trait:

Not all traits are autosomal, some are carried onthe unmatched X and Y chromosomes. These traitsare called sex-linked. Most are carried on the X.

They are inherited differently in males and females.

The male chromosome complement is XY. A malecannot be heterozygous for an X-linked trait. Thereis no way to ‘hide’ recessive traits. Therefore, sex-linked recessive traits are much more frequentlyseen in males (their phenotypes) than females.

Examples of X-linked recessives:

red-green color confusion hemophilia

Chromosome abnormalities:

fragile-X syndrome - most common genetically caused mental retardation. A part of an X chromo-some “hangs by a thread”. More common in malesthan females. Effects partly determined by the parentproviding the fragile X chromosome.

arrow marks the fragile region

Retardation is more common if the fragile X camefrom the mother, and is more common in males. Is it sex-linked?

The reason for fragility is a much multiplied triplet CGG repeat sequence (usually ~30x, in fragile X 100-1000s of times. Up to ~200 repeats there may be no retardation. But the number of repeats seems toincrease when a woman passes the repeat segment toher children.

So, it is sex-linked, but not in a simple Mendelianway.

In addition to mutations that can cause cancer,retardation, or various diseases, there can also be abnormalities in chromosome number. This is usually due to an error in meiosis producing either sperm or eggs.

Because a female’s eggs only complete meiosisyear’s after it began, scientists believe that chromo-some abnormalities are far more likely in olderfemales than in males.

The most common error in humans is trisomy 21 -presence of (in whole or part) a 3rd copy ofchromosome 21. Caused by non-disjunction duringmeiosis. Severity of resulting Down’s syndromedepends in degree of trisomy.

Other relatively common chromosome numbererrors occur in sex chromosomes. Why?

Non-disjunction in X:fertilized by Y-bearing sperm - XXY Kleinfelter’s syndrome - externally male, but sterile, and may have some breast developmentfertilized by X-bearing sperm - XXX trisomy X - mostly normal, fully fertile, but may have abnormal menses

What about an egg which gets no X chromosome?

fertilized by Y-bearing sperm - -Y aborted in early development, genes on the X are required for survival and development

fertilized by X-bearing sperm - -X Turner’s syndrome - thickened skin fold alongside the neck, otherwise normal in appearance, but female sex organs and secondary sexual characters do not develop at puberty, sterile. Only about 2% develop to birth, most are auto-aborted.

What about non-disjunction in Y chromosome?

if it fertilizes a normal egg - XYY “supermale” - taller than average, possibly (??) slightly lower IQ, some controversial evidence of a tendency to aggressiveness and a higher than expected presence in prison populations

Sex chromosome compliments were also used in Olympic sex testing. How?

Females are like calico cats. In each cell (normallyrandomly) one of the X chromosomes is inactivated.It remains condensed and is bound to the nuclearmembrane. The condensed X chromosome is calleda Barr body.

Males, with only one X, need it active.

Testing involves taking a scraping from the inside ofthe cheek, putting the cells on a slide, and stainingthe DNA. If there is a condensed chromosome (aBarr body), the individual is a female. None andhe is excused from competition.

This is what a Barr body looks like:

There can be problems with this determination.A few rare females (XX) carry, by translocation, the male determining gene from the Y on at leastone of the X chromosomes. They would appear tobe males, have approximately male muscle develop-ment, and apparently even have an enlarged, penis-likeclitoris.

And some males (XY) may, by missing a burst oftestosterone normally produced by the embryo inutero, develop as females externally, and even tothe point of having a (non-functional) uterus.

How should society deal with these individuals?These last questions remain unresolved, but modernmolecular testing at least tells us how the testedindividuals function.

Translocations - Pieces of chromosomes mayend up attached to different places than normal.One example: a section of chromosome 22 attachesto chromosome 9. Result: chronic myelocyticleukemia, a form of cancer.

Finally, let’s look at one of the more importantpoint mutations important in the human genome -the sickle cell trait.

Sickle cell anemia is caused by a single base changein the DNA for a protein chain in the hemoglobinmolecule. The result is replacement of one amino acid (a glutamic acid replaced with a valine).

There is only a slight effect if an individual isheterozygous. Some sickling occurs if the individualis exposed to low oxygen. About 9% of African-Americans/Canadians are heterozygous.

The situation and effects are much more serious in those who are homozygous for the altered gene.

The sickling of red blood cells when oxygen isnot bound to the hemoglobin. It causes these cells tostick in capillaries. That causes damage in variousorgans (e.g. liver, kidneys, and brain); joint problems…

The disease used to be fatal by early adulthood. Nowpeople survive into middle age.

Why does a gene that causes such severe problemspersist?

There are at least two reasons: 1) Being heterozygous confers a greater resistance to malaria. Where the gene is found at high frequency, malaria was a severe problem, and remains widespread.

2. Women who are heterozygous for the sickle cell gene are more fertile (are more likely to have children, have more children) than those who lack the gene. Of course, those who are homozygous for the gene will have great difficulty with pregnancy and birth.

Therefore, even where malaria is not a problem, e.g. North America, the gene persists. This is oneof the reasons for the importance of geneticcounselling for those who may be carriers of anyof a large number of genetic diseases.

There are tests available during pregnancy that canspot literally hundreds of chromosome or biochemicalabnormalities.

Amniocentesis - amniotic fluid from within placenta extracted, cells in it cultured, tested for chromosome abnormalities and/or suspected biochemical problems Performed at 15-16 weeks into pregnancy.

Chorionic villus sampling - cells from the fetal part of placenta extracted and tested. This test can be performed earlier in pregnancy (6-12 weeks)

Now back to the inheritance and expression ofhuman traits -

Mendelian genetics is relatively simple. The situation for most human traits is not quite thatsimple. There are complications.

Expressivity - the same gene may be expressed differently in two individuals. Reasons may include environment, genetic background (the other genes), …

Penetrance - the likelihood that an individual carrying a dominant gene will express it. Some traits with incomplete penetrance will be expressed in only a fraction of individuals.

Pleiotropy - one gene may affect many traits. Remember all those effects of sickle cell trait. The same sort of thing occurs with a 3 base deletion in the gene for a transmembrane protein that pumps Cl- out of cells. The defective protein leads to cystic fibrosis, affecting lungs, sweat, digestive glands (particularly the pancreas), and sex organs.

Most (virtually all) traits are polygenic. What we see in the phenotype is the joint result of the actions of 2 or more genes. Eye color results from 2 genes - one determines whether pigment will be produced; the other determines how much.

Multiple alleles - the Mendelian traits we looked at had only two alternative alleles. Many traits have more than 2 possible versions. The classic example is blood types. There are 3 alleles involved in ABO blood group determination: IA , IB , and i.

These alleles determine the presence of antigenic proteins on the surfaces of red blood cells. IA causes the presence of A-type glycoprotein on cell surfaces. IB causes B-type glycoprotein. i does not cause an effective antigen to be present.