This is our second podcast on our human genetic series and I'm presenting this
just to provide you with some general background information. We'll start this
by considering development. Development is the slow process of progressive
change in the descendants of a fertilized egg, which will give rise to a
complete human being. And during development, the genome interacts with
the extracellular environment to produce changes in the cellular phenotype. And
you know from your study of embryology that these changes are orderly and
they're time dependent. And in 1926 the great biologist EB Wilson said, "that the
characteristics of an organism gradually emerge by the utilization of inherited
information that is located on the chromosomes." That's a pretty extraordinary
statement to be made so early in the 20th century. And here, if you think of
genetics just with a brief historical perspective, we can say that modern
genetics began when Mendel's work was rediscovered in probably 1900. Human
genetics as a scientific discipline probably took fruit in the 1950's after
the second World War. Clinical genetics or medical genetics,
which is a branch of medicine, began in the 1960's and that kind of encompasses
research into genetic disorders and its application in diagnostics and genetic
counseling and management. Here are some key terms that I think
everyone has heard of in relation to genetics and I put these in the context
of some major things that have happened in the history of science. So, we know
that, for example, Darwin and published his Origin of Species in 1859. Mendel was
doing his work in the 1860's and he came up with the terms dominant and recessive.
In the early part of the 20th century, Bateson termed concepts of homozygous
and heterozygous and then you can put this in the context of understanding
genotypes and phenotypes. Again, in the early decade of the 20th
century, wasn't until the 1930's and 40's that people realized that DNA carries
genetic information. Watson and Crick of course did their
groundbreaking work and published their paper on the double helix in 1952. And of
course, the cell cycle was finally recognized with the Nobel Prize for
Hartwell, Hunt and Nurse. In the turn of the 21st century, the human genome
project, of course, completed the first draft in 2003.
So, our first effective definition of a gene the smallest particle representing
one hereditary characteristic in the early 1900's. That allowed advances to
occur and the understanding of genetic processes without requiring any
knowledge of what genes actually were or even how they worked. A modern definition
of a gene, this is around the time of the 1990's, we think of a gene as a region of
genomic DNA sequence corresponding to a unit of inheritance, which is associated
with regulatory regions, transcribed regions, and other functional sequence
regions. If we think about the human genome, we have a haploid chromosome set
and our human genome would consist of our nuclear DNA and our mitochondrial
DNA. Our nuclear DNA is relatively complex, whereas our mitochondrial DNA is
fairly simple. Our nuclear genome is on 22 autosomes
plus the X or Y chromosome and there are approximately 25,000 genes described in
the human genome. That constitutes about 2% of our nuclear DNA. The majority of
our nuclear DNA is considered non-coding DNA. Of the 25,000 genes, there are
perhaps 22,000 protein coding genes and maybe about 3,000 RNA coding genes. This
is not a bad time for you to consider reviewing materials on gene organization,
satellite DNA, transposons, structure and function of nucleic acids, and
chromatin structure. And you should be able to review these from your
coursework in biochemistry, molecular biology, and/or cell biology. Now, when we
think about genetics we're generally thinking about it in relation to
reproduction and consequences to subsequent generations, but there are of
course developmental issues that relate to genetics and we might talk about
mitotic inheritance. We clearly know about and talk about stem cells and if
you haven't appreciated this yet we'll talk about X chromosome inactivation. And
here I'm just giving a broad overview because these things will be covered in
more detail through our course. But if we think about mitotic inheritance, we can
think about differentiated cells like fibroblasts or lymphocytes and here
mitosis produces two identical daughter cells. And if these cells continue to
divide, they're gonna transmit the same act of genes to all succeeding
generations. This implies that in differentiated cells some specialized
genes are going to be turned on while others are gonna be turned off. So, it's
clear, that's why a fibroblast is different from a lymphocyte with respect
to gene expression. If we think about stem cells, we know that undifferentiated
cells can undergo mitosis but they might produce two different populations of
daughter cells. You might have a differentiated cell and another
undifferentiated cell and this cartoon just highlights that, that the cells
might divide and form stem cells, some of these cells may differentiate to have
different potentials. And of course, we know about X chromosome inactivation. The
so-called lion hypothesis and this indeed relates the dosage compensation.
You may realize that in early embryonic development, one X chromosome becomes
randomly inactivated. These two chromosomes are going to have
DNA sequences but they're gonna have different parental origins. So, early in
embryonic development some cells are going to randomly inactivate either
maternal or paternal X chromosomes. So, human females would, in a sense, be
mosaics with respect to which X chromosome is expressed in which cell.
And we know that in some cells you find a borrow body. The borrow body is the
representation of the inactive X chromosome. Now, females will produce
X-linked gene products in quantities that are relatively similar to those
that are produced in males that have only one x chromosome. That's because all
of the genes on the inactive X chromosome are turned off, or I should say,
most of the genes are turned off and that's going to require special gene
products and we'll talk about that later in our course. If we think about
embryonic development, we can think about it being controlled by differential gene
expression that would have genetic factors and we can think about
environmental factors so-called epigenetic factors. And basically, if you
think about embryonic development and differential gene expression, we can say
the differential gene expression requires that the right gene be
expressed in the right place at the right time. I like to think of this in a
simple-minded way, during development and throughout life genes might come in two
varieties: they'll either be genes that are turned off or there'll be genes that
are turned on. Developmental genes have turned on early in embryogenesis and
have subsequently turned off and generally remain off later in fetal life
and postnatal life. On the other hand, tissue specific genes may be turned off
early in embryogenesis but are turned on at the right
time and in the right tissue throughout life, whether it's embryonic life or even
through adult life. Besides developmental genes, there are other important genes.
You've heard about these in biochemistry and in molecular biology.
There are housekeeping genes, mitochondrial genes, tumor suppressor
genes, and oncogenes. We've heard of non-coding DNA, which is structural DNA.
Some people even think there is junk DNA, DNA that doesn't serve any function. And of
course, only about 2% of our DNA is coding DNA. This is a cartoon or a series
of cartoons from quite a bit ago, 2003 from Time magazine but it's just to give
you a sense and you appreciate all of this how genes get switched on and how
they're transcribed. You know about enhancers and promoters and it's just to
let you realize that much of this is in the common everyday language of people
how genes are turned on and how they're not, how they're activated and it's going
to be important for you as physicians to have a good understanding of this to be
able to explain in simple minded terms to your patients. Something that we're
beginning to appreciate is epigenetic inheritance. This is where cellular
information other than DNA sequence may be heritable during cell division. So, we
can talk about modifications to genes other than to changes in DNA sequence. So,
things like DNA methylation, histone acetylation, RNA interference. These are
all things that can affect gene expression and can influence epigenetic
inheritance. And again, from the popular press, there's an article in the 2013
December issue of Smithsonian magazine that talks about toxins that affected
your grandparents might actually be manifest in second and even third
generations. And then, there's an article in The
Scientist early in 2015 that talks about social adversity may shape people's
immune systems and susceptibility to disease. That's a fascinating article
that even talks about how people that were in the concentration camps in World
War II could have been under such adverse conditions of stress that it
would have negatively impacted their immune systems and could have led to
subsequent disease in later generations. We know about DNA methylation, so you've
probably heard about this in biochemistry. At 6 weeks of development,
there are different sets of globin genes that are expressed, as opposed to what
goes on at 12 weeks of development. So, for example, at 6 weeks the epsilon
globin genes are active, the gamma globin genes are inactivated because their
promoters are methylated. At 12 weeks the reverse happens, the epsilon globin gene
promoters get methylated and the gamma globin genes become demethylated, so the
gamma globin genes are active at 12 weeks. We'll talk about genomic
imprinting. This is a rare form of gene regulation in which one allele of a set
of autosomal genes are silenced and this emphasizes the importance of both
alleles for normal development and function and we'll see some examples of
imprinting that relate to some rare genetic disorders as our course
progresses. And I think you appreciate from embryology that all cells require
both maternal and paternal chromosomes for normal development. Usually we
associate genes on the paternal chromosomes with growth and genes on the
maternal chromosomes, we usually associate with growth suppression. Now,
let's put some genetics background into the context of disease. So, we know that
there can be genetic causes of disease and these may be able to be understood
fairly easily. We know there may be environmental causes of disease
and this may or may not be understood so easily. We also know that there are
multifactorial causes of disease. So, many diseases have both genetic and
environmental factors. We might consider something like a myocardial infarct. So,
we could think of things like hyperlipidemia, arthrosclerosis, plaque,
rupture, or clot formation, and all of these may lead to a myocardial infarct.
So, we can think of genetic issues that would relate to lipid metabolism. We can
think of genetic factors that might help to maintain the structural integrity of
blood vessel walls or that might lead to plaque formation. We can think of various
clotting factors and all of these coming together may influence a myocardial
infarct. There are clearly environmental factors like smoking, diet, exercise, or
lack thereof of potentially infection that might relate to any of these steps
along the path to myocardial infarction. And, there are clearly other diseases
that can lead to potential problems that might relate to a myocardial infarct
like hypertension or diabetes or obesity. So, what I'm trying to suggest just as
some background information and we'll see this throughout our course, that if
you look at ideologies of disease there may be chromosomal causes of disease,
there could be genetic causes of disease that may relate to single gene defects
like dominant or recessive or sex linked conditions. We'll certainly talk
about these in our course. There may be a typical or non-mendelian genetics actors
that can relate to disease. We'll clearly talk about mitochondrial genetic defects
that can relate to disease. There are environmental factors that can relate to
disease. And as we've suggested, many ideologies of disease may have
multifactorial causes.