GENETICS FOR THE PERPLEXED WEEK 1

BASIC MENDELISM

What are the definitions of Mendel’s first and second laws?

First law (the law of segregation): Two alleles at a locus segregate into separate equally into
the gametes; half carrying one allele and the other half the other.
Second Law (the law of independent assortment): During the formation of gametes, the
segregation of alleles at one locus is independent of that of the segregation of alleles at any
other locus.

These are the formal definitions. All they say is that genes are particles, and that genes for
different characteristics such as colour or shape are inherited independently of each other.
Today, we know that the second law can only be true if the loci are on different
chromosomes.

In your lectures, why do you not use a CAPS to donate a Dominant allele and a little letter
for a recombinant allele, so the heterozygote for pea colour is Yg?

No real reason, it is just a matter of preference. As a note, some alleles can act as both
dominant and recessive, depending on the trait/phenotype you are looking at. An example
can be seen in lecture 3 with the Manx cat, see next week’s Genetics for the Perplexed for
details.

Can you define the main genetical terms, please; eg “locus”.

Gamete – is a sex cell; includes sperm and egg in animals or pollen and egg in plants
Zygote – a fertilised egg
Locus – the location of the chromosome at which a particular inherited attribute – pea
shape, pea colour – is located
Allele – the alternative forms of information present at that site
Homozygote – has two copies of the same allele at a particular locus
Heterozygote – has two different alleles at a particular locus
Dominant – an allele which is fully expressed in heterozygotes and homozygotes
Recessive – an allele which is only expressed in homozygotes.

What does progeny mean?

Offspring, children, infants, etc

What is a locus and an allele?

Locus - the place in the genome where genetic information for a particular attribute is coded
– the locus for pea colour, or the locus for pea shape; or the human ABO locus for that
matter. Allele – the alternate forms at that locus; round or wrinkled at the pea shape locus,
for example.
If both parents are heterozygous for a recessive allele, the probability of any child being
affected is 25%. However if the first child is affected, would the chance of the second and
the third child being affected still remain 25%?

Yes; they are both independent events.

In the book and course notes, they state that " we always assume the person marrying
into the family from outside is A/A." Why?

This is an assumption that we make if we do not know the genotype of an individual

marrying into a pedigree. In large part, we disease alleles we are interested in are rare.
Therefore, if you do not know the genotype of some unrelated person coming into the
family of interest from outside it is customary to assume that the individual is homozygous
for the most common allele in the population. So if it was a pedigree on cystic fibrosis
people marrying into the pedigree would be assumed to be AA – a homozygote for the
normal dominant allele. This is not ideal, but is normal in working out pedigrees, at least in
the first instance and makes the maths simpler. Later in the course, when we deal with
Hardy Weinberg, you would be able to consider what probability the unknown person is of
being a heterozygous carrier (in the case of a rare recessive such as cystic fibrosis) being
given the frequency of the allele in the population. But let’s keep things simple for now.

I haven't completely understood whether a dominant allele for a disease is Aa or AA.

An allele is ONE (not two) of the alternative forms at a locus. Conventionally the capital A is
used to describe the dominant allele while the little a describes the recessive. In your
question, if A is dominant, then both the homozygote AA and the heterozygote Aa will show
the disease phenotype. However, for some diseases covered on this course, such as
Brachydactyly, they are lethal as homozygotes. Basically an individual can survive a single
dose of the allele, but not a double dose of the allele. Therefore in the brachydactyly
pedigree you know that every individual is a heterozygote.

Related to the previous question, if a disease has an autosomal dominant pattern of

inheritance, will the inheritance of 2 dominant alleles always be fatal or are there
exceptions to this rule?

Some diseases the dominant homozygote is lethal before birth (eg achondroplasia); in
others it is not (eg Huntington’s disease). There is no set rule in human genetics and it
depends on the underlying biochemistry of the disease.

How can a locus be heterozygous? Surely the alleles are the ones that are heterozygous,
and they are found at the same locus on each chromosome.

No, the alleles are the single “particles”, the locus is the site where those particles reside.
You can be heterozygous for the alleles A and B at the ABO blood group locus, making you
an AB heterozygote.

What is a dihybrid cross?

Just another word for a two locus cross, as in Mendel’s second experiment.

If one parent has two dominant genes and the other has two recessive genes then the
ratio of the phenotypes of the f2 children will be 9:3:3:1. Does that mean that the chances
of them having a child with both recessive genes is 1/16?

Again, the G word! You mean two dominant alleles, not genes (although admittedly we do
sometimes use that dubious term in a loose and general sense). Yes, if there are two loci,
each with two alleles, then the chance of having a F2 offspring homozygous for recessive
alleles at each of the two loci is indeed 1/16 (which is 1/4 multiplied by 1/4).

How did Mendel get such accurate results as to get the ratio 9:3:3:1?

Well, some people say that he (or his gardener) cheated: ie he had, in later experiments,
worked out what he expected to happen, and consciously or unconsciously manipulated his
results to fit. Others, though, dispute this; they say that modern statistical tests in fact
accept that the figures he used are acceptable given the size of each pea family and the
influence of random sampling. Personally, I don’t really care, what he worked out continues
to amaze me. The important point is that he was right!

How do you do chi-square? What is a Mendelian model?

Chi-square is just a way of assessing whether counts of a particular variable (such as the
counts of yellow vs green peas) deviate from a hypothesized ratio. Mendel did his crosses
on an industrial scale, and it would be highly unlikely to get exactly a 3:1 ratio in his first
cross. Most likely is that it would approximate a 3:1 ratio. The chi squared test is a way to
determine if the observed ratio was significantly different from the 3:1 ratio or could be
explained by just random sampling/chance alone.

We will use chi squared in later tutorials (not for tutorial 1) chi-squared test in the tutorials,
but in brief you first have to calculate a chi squared test statistic:

Just looking at the formula, you can see how it roughly works. If we observed the exact
same observed value to our expected value, the chi squared value would be 0. As we
increase the difference in the observed and expected value, the value of the chi squared
value will also increase. Let’s go through a worked example:
Let’s say we did Mendel’s first experiment and got 80 yellow (wild-type) peas and 10 Green
(mutant) peas. Does this differ from the expected 3 wild-type to 1 mutant (3:1) ratio?

We have our observed counts, we need to work out what numbers we would expect under
a 3:1 ratio:

Wild-type: (80+10) * 3/4 = 67.5

Mutant: (80+10) * 1/4 = 22.5

Therefore:

The chi-square test statistic is compared to critical values. To cut a long story short, the
critical value when there are 2 groups is 3.841. If the test value is greater than the critical
value, we know that the values deviate from the predicted 3:1 ratio.

Need some refreshing on drawing out dihybrid crosses please. Mendel's second law:
explain the ratio of 9:3:3:1 (it seems confusing to me). Is there an equation for working
out combinations of gametes?

It’s really just pulling beads out of a bag, if the beads are alleles at a locus. You have a bag
with 500 black and 500 white beads in it. To model a single locus with two alleles pull them
out in pairs (forget the random accidents of sampling); and you can get BB BW and WW –
which is equivalent to having a single locus with two phenotypes (black and white if B is
dominant to W) and the three genotypes homozygous B, heterozygotes, and homozygous
W.

For two loci, you have two bags; the second has 500 reds and 500 greens in it and red is
dominant to green. Take out 2 from the first bag, and put 2 from the second bag next to it.
There are 16 possible combinations:

BR BG WR WG

BR BBRR BBRG BWRG BWRG

BG BBRG

WR
 WG

AND SO ON – FILL IN THE SQUARES YOURSELF

Count them up, and you fill find 9 different genotypes (see, for example, the two copies of
BBRG above). If we regard the balls as alleles, and bags as loci, and there is dominance, you
will have 4 phenotypes – black red, black green, white red, and white green.

The general rule, from the simple laws of probability is that with n loci use the formula 2 n for
the number of phenotypes and 3n for the number of genotypes – if there are 2 loci that
gives you 4 phenotypes and 9 genotypes in the F2 after recombination and if there are 3 loci
you get 8 phenotypes and 27 genotypes and so on.

What is the symbol if a pair of non-identical twins are of the same gender?
I have encountered a couple of ways that monozygotic twins are presented in pedigrees
compared to dizygotic twins. You are right that they can be considered genetically the same
in a pedigree, but they do actually have their own symbols. See below:

I am not such a fan of the above method as it implies that the monozygotic twins mated
(eww). I prefer the one below:

Is it worth doing something like 23and Me?

No, they are a complete waste of money. A lot of statements you come across in these
companies are either greatly exaggerated or simply nonsense. Saying something like the test
showed I have Viking ancestors is garbage and is no better than astrology. You hear these
stories in newspapers a lot. Truth is there is little scientific basis to these claims.

You only have to go back 5000 years. Everybody alive at that point of time is either an
ancestor to every individual alive today, or of nobody alive today. This is a blink of eye in
terms of human evolution. Go back just 3500 years before somebody who lived who is an
ancestor to every individual in the world today. I wouldn’t even call 3,500 years a blink of an
eye, it is so dam close to the present day. To give some context humans left Africa 50-60
thousand years ago, and by 10,000 years ago, the entire world was basically colonised.

This basically means everyone alive today is the descendant of Vikings, romans, Asians,
Arabs, whatever. Ancestry is complicated and messy; a lot of these companies claim this
section of DNA is from roman times, but this is just storytelling. Of course the Roman DNA
would itself be a hodgepodge of DNA from different origins. They provide no more than a
vague hint of where your ancestors might have lived.

There are also ethical issues that I do not think we as a community have discussed enough.
We have paid a commercial company to take our genetic data, which will be around long
after you have dead, it is owned and will be sold by the company which has it.

If Mendel’s traits were on the same chromosome, would he still get the 9:3:3:1 ratio?

No! Mendel was SO lucky in this regard, but I guess you would need a bit of luck to work out
the second law. As luck would have it, it turns out that all of Mendel’s 7 traits that he looked
at were on different chromosomes. I am going to illustrate this with a dihybrid cross with an
A/a locus and a B/b locus. In the first scenario, we will have our two loci on different
chromosomes, a red chromosome and a blue chromosome. Remember you have two copies
of every chromosome, one from each of your parents:

This was essentially the scenario Mendel had for all his traits. Because each loci was on a
different chromosome, it means each allele independently assorts ie the A allele has an
equal chance of landing in a gamete with B or a b allele. We would get a 1:1:1:1 ratio of
gamete genotypes: AB Ab aB ab

However, how will the ratio of gametes change if the loci are on the same chromosome?
This will be addressed in lecture 6 (it is termed ‘linkage’), but let’s simplify it here:
The scenario when the loci are on the same chromosome is different. This is because during
meiosis and the formation of the gametes, crossing over (called ‘recombination’) occurs
between sister chromosomes (ie the equivalent maternal and paternal chromosome).
Putting it again simply, the probability of this occurring between our A and B loci is very
small. Therefore in terms of the frequency of the gametes, we are going to be observing a
relative increase in the proportions of AB and ab gametes (we call these the Parental
Gametes as these would have been the same gametes as the Parentals, P 1 produced). The
only way we can get a B allele paired with an a allele and a b allele paired with a A allele is if
the crossing over event occurred between the two loci, with is not very likely (again we are
putting this very basically, I will re-do these diagrams in the future to give a fuller account!).
This means we will observe a relative decrease or deficiency in the aB and Ab genotypes
(which we call recombinant gametes, as these would not be produced by the original P1
individuals).

Were Mendel’s loci closely linked, it would have played havoc on this Second experiment.