Lecture for 23.030.2020 to 27.03.

2020 Week

Mendelian Genetics: Genetic Disorders

Welcome to the set of lectures on ‘Mendelian Genetics’. Mendelian refers to Mendel, Gregor
Mendel. We will refer to him during the course of this lecture and it will also become clear to
you why we are looking at something that is so old. What is the relevance nowadays?

Many diseases have a genetic basis. You know that each cell in the body has the same set of
genes; each somatic cell in the body has the same set of genes, and it does not matter whether it
is the brain cell or the liver cell or a skin cell and so on so forth, they all have the same set of
genes that we inherited from our parents.

They could be expressed differently depending on where they reside and so on and so forth, we
will not get into that. But, the basic material is the same. And since the same genes are present in
every single cell throughout the body, genetic diseases will manifest across and there is nothing
much can be done, it can only be managed. It is rather difficult to cure them as yet. Genetic, or
gene therapy has some promise, it is , it has been studied for quite a long time; it has had a few
successes, but I think it needs quite a bit of development before it gets to a good acceptance
stage.

Let us start with some data. In India, an estimated five thousand two hundred infants with sickle
cell disease, nine thousand with something called (beta) beta thalassaemia, twenty-one thousand
four hundred with Down syndrome and (thirty-nine), three hundred and ninety-thousand with
G6PD deficiency are born each year, okay? These terms, some of which we have seen earlier;
sickle cell disease you know, sickle cell anemia, the same thing, it is called sickle cell disease. If
you want, you could look at this video, which is also given in the pdf file, which can be clicked
from the pdf itself. This is an optional video to know about sickle cell disease, nice video, but it
is an optional video.

Similarly, you could look at this video for knowing what thalassemia is, especially beta
thalassemia; there is alpha thalassemia and beta thalassemia, you could click on this, again an
optional video. Down syndrome, I would suggest that you watch the first three minutes of this
video. It has a very nice overview of the genetic basis itself, and it gives an introduction to the
Down syndrome, and then it gets into a lot of research aspects, that might be a little beyond this
course, the research aspects, the first three minutes are very nice, I would recommend that you
watch this, the first three minutes of this video.

And then there is something called G6PD deficiency which seems to affect a large number of
infants born every year, right? This is a social aspect that is given, an optional video, and this is
an allele view that is given of G6PD deficiency, which you may want to look at, okay? These are
optional. Except the first three minutes, I would say is highly recommended. This is actually
from a source because these are numbers and these are estimates; this is actually from a source,
a paper published in two thousand two by Verma and Bijarnia; ‘The Burden of Genetic
Disorders in India and a Framework for Community Control’. It was published in ‘Public Health
Genomics’. This was in two thousand two, the numbers, of course would be different now, but
atleast we have something that we can hold on to, in terms of numbers. That is why this is
chosen. Gives you an idea of the prevalence of such diseases in India.
We have already seen the sickle cell disease; let us review this. We know that normal
haemoglobin is made from the haemoglobin, haemoglobin is a protein, therefore it is made from
the genes that correspond to the various sub-units, that code for the various sub-units. In a
normal haemoglobin gene, there is a glutamic acid in the sixth position. If that glutamic acid
becomes a valine, right? If, if that is changed, then just that one change can bring about a
different conformation, different three dimensional folding in the case of the various protein sub-
units, and we get a haemoglobin molecule that can easily crystallize out, it will not have an
ability to carry oxygen as a normal haemoglobin molecule does.

And therefore, we get sickle cell anaemia, right? This is, it is as simple as that. The, if the
haemoglobin is normal, the red blood cell would look nicely disc shaped, and if it happens to
have, if it happens to be diseased with sickle cell anaemia, then the red blood cell takes on a
sickle shaped, sickle shape. And this causes major difficulties as you have already seen in an
earlier video, in an earlier recommended video in this course.
Similarly, thalassaemia is incorrect sub-unit formation in haemoglobin; either the alpha sub-unit
or the beta sub-unit are incorrectly formed, it is different from sickle cell anemia. Down
syndrome is caused by an extra chromosome number twenty one. Typically people have two
chromosomes, right? The chromosome twenty one has three; there are three number twenty one
chromosomes. If that happens, this happens in each cell, if that happens, it results in Down
syndrome, and it manifests in different ways that you can pick up from the video that was
recommended, that was suggested, it is an optional video.

And then, this G6PD deficiency, which stands for ‘Glucose 6 Phosphate Dehydrogenase’
deficiency, this enzyme is faulty; and because this enzyme is faulty, it leads to a lot of
difficulties, major difficulties, right? Again recall that ‘Glucose 6 Phosphate Dehydrogenase’; It
is an enzyme, which means it is a protein, it is coded by a gene, right? And therefore, it is a
genetic disorder. This is in India. In other countries, cystic fibrosis; it is a very very common
genetic disorder in the US; it arises because the channel for chloride in the membranes
malfunctions, okay, because the protein which is actually the chloride channel protein, that is not
properly formed and therefore, that malfunctions, the chloride cannot move in and out of the cell.

If that happens, there is a chloride build up in the extra cellular space, and that results in mucus
build up, reduced resistance to infection, and without proper intervention, death usually occurs
below five years of age, okay? With intervention, people live much longer, and it affects one in
two thousand five hundred Americans, it's a very prevalent. You can look at this video which
gives you some idea of cystic fibrosis, it is a let us say an optional video. And similarly,
Huntington’s disease, which actually manifests above forty five, is a genetic disorder.
Achondroplasia, which is a kind of dwarfism, okay. You might recall Peter Dinklage, from
‘Game of Thrones’, right? Tyrion Lannister, is it? , that person, has Achondroplasia; it is a type
of dwarfism. That is an inherited disorder; a special type of inherited disorder as we will see
later.

Now, we said all this for this reason: if we can predict a child's chances to inherit a disorder,
okay, something as major as cystic fibrosis, the parents can be informed to handle it in their
child, okay? They will be atleast expecting this difficulty in their child, they would be mentally
prepared to handle it and so on and so forth, in their own ways, and that would be a big thing,
that is already being done, and the basis for that is what we are going to see in this particular
lecture.

A simpler way to do the predictions and the element analysis, we know a lot today and there are
various ways to do this analysis; but a very simple way in which this analysis can be effectively
done is by using the principles of ‘Mendelian Genetics’, and the principles of Mendelian
Genetics evolved, may be a century and a few decades ago, when inheritance was not even
understood, when people did not understand how, what is the basis of the son or the daughter
looking like their father or the mother, and sometimes looking like their grandmother or the
grandfather and so on and so forth. People just did not understand.

Right? It was during that time, late eighteen hundreds, that these principles were developed; we
will very briefly look at it by Gregor Mendel, seminal piece of work, and those principles are
very effective today, although they are, you know basal principles and there are huge variations
known to them, those principles are still very useful to do this, to be able to predict a child’s
chances to inherit a disorder; and that is the reason we are studying or we are looking at
Mendelian Genetics even today.

In any case, historically it is nice to know what Mendel did and the development of that if you
are interested in genetics; but there is a very useful angle to it. When inheritance was not
understood, may be a century ago, the inheritance of characters, of course has always had a good
appeal with people. People were always curious to know why people inherit characters, why a
son behaves like the father or the mother, or the daughter behaves like the father or the mother
and so on, or sometimes even like the grandfather or grandmother.

Many felt that there was always a blending of traits; there was some trait from the mother, some
trait of the father, the son or the daughter has, or the offspring has the traits that are a blend of
these two traits, that was what was believed for a very long time. Although, there were many
different situations where this clearly was not valid, okay. That has always puzzled people but
they were skeptic about it and so on and so forth, till Mendel came and told us that the traits are
actually passed on by trait particulates. There are aspects that determine traits in an appropriate
fashion and if you understand this, you can predict to a certain extent what will happen.

So that was a big contribution by Gregor Mendel, and I would like you to watch this very nice
video. I would I would say it is a required video; it is a very nice video, slightly long, about
twenty, twenty five minutes; so long, old, but it is a very nice video, okay, I would like you to
watch this video to know some parts of Mendel’s life, which is very interesting and Mendel’s
experiments and some of the principles that he brought forward, okay? In this lecture, or these
set of lectures, we will see what is relevant for us.
To do that, we will have to map our current terminology to the terminology that existed during
the development by Mendel, okay, or, soon after that for many years. To do that, let us consider
cystic fibrosis. The presence of the chloride transporter is important, because if that is absent,
cystic fibrosis arises. There are two possibilities; the membrane protein for the chloride
transporter, is either functional or the membrane protein for the chloride transporter is not
functional, right? These are the two possibilities, normal or cystic fibrosis.

The presence of the chloride transporter is a character or a heritable feature, okay? Heritable
feature is called the character. Sometimes it is not as, not in molecular terms as this, it could be
the height of a person, or it could be the colour of the eye, and so on and so forth. Those are
typical observable traits, or in other words, the characters usually an observable thing, I am just
using a terminology mapping here, so this aspect, if it can be observed, it is called a character,
and it is a heritable feature.

The variants of each character, each one of them is called a trait. Okay? For example, the
functionality is a trait, the non functionality or the absence is a trait. Tall is a trait or short is a
trait, okay? Blue colored eyes is a trait, brown colored eyes is another trait, and so on. So, if the
character happens to be eye colour, blue eye colour and brown eye colour are the two traits, or
many, two of the many traits of that particular character. If height of something is a character,
then tall is a trait and short is another trait, and so on. You get the idea.
So we are going to deal in terms of characters, traits and so on. Each trait is determined by two
alleles on homologous chromosomes, and this is what is equivalent to the genes that we know of,
right? On homologous chromosomes means, you know that they exist in pairs and therefore, we
just talked of pair number twenty one, if there is an extra one, that’s Down syndrome and so on,
but those two twenty ones or those two twenties or those two, let us say one two three, they are
all homologous chromosomes; and two alleles on homologous chromosomes determine each trait
is the equivalence here.

So if these two are homologous chromosomes, capital T is an allele, and small t is another allele.
So you could have various combinations, both could be capital; they could be alternate, one
could be, this one could be T, this one could be small t, or both could be small ts. And these
different combinations result in different traits of that character; different yeah different traits of
that character. The position on the chromosome of that allele is actually called a locus, this is just
for the terminology, okay?

Remember that this is a simple approximation, there are variations possible, we will point them
out when we come to them. I think at this point in time, we will take a break and cover the other
things in the next lecture. It will be very nice if you can see the recommended video or the
required video on Mendel and his work, we will see that, okay. And then, let us meet in the next
lecture to take things forward. See you then.