Lecture 1:  Introduction:   -General Principle; Mendelian Genetics

Simplistically, Genetics is a study that analyses the factors that underpin the rhythm of change and potential variation in all living organisms -the mechanisms by which these rhythms are maintained, how they came about, how similar they are to each other and how they are distinct.

As such, it blends mathematical approximations of observed phenotypic traits, and to a large extent data based informational analysis with a keen determination of the very fabric of organismal organization.

Curiously, in pursuit of this global appreciation of how life functions the study of Genetics has raised -and continues to raise- questions about our true understanding of our genetic world.

Even so, In the last thirty to forty years or more this understanding of Genetics has given rise to dramatic break throughs in medicine... and, indeed, how our very genomes are arrayed and structured.

1978 first "test-tube baby ...             2016 First "3 parent" baby is born...         Bioethical concerns abound...

1984 DNA Fingerprinting...          1997 E.coli genome sequenced...       2001-03 Human Genome sequenced(?)

                                                                        

2010 first synthetic organism (Mycoplasma)      2015- micro RNA's and editing genomic DNA in situ (CRISPR).

Today, of course we are all mired in the midst of a pandemic, which defines the "genius" of genetics at work in a viral life cycle that doesn't even use the traditional "central dogma" that we will tout in the next few lectures.

2019 Sars-CoV-2 pandemic
     

As such, Genetics continues to challenge many of the tenets that have been the mainstay of the science for the last 60 years, daring to suggest that -at the very core of our genetic makeup- the classical genetic dogma of DNA replicating and being able to give rise to transient RNAs that interact to produce proteins which provide most of the important functions in the cell -while important- is potentially a "side show" to the true mechanisms of gene expression in many cells.

Classical Geneticists, and now Molecular Geneticists are able to address the consequences of genetic activity at the genotypic level. Thus, they infer mechanism and genetic order from an "understanding" (rationalization) of gene function and (as we have discussed) can even begin to effect changes in the genetic makeup of higher organisms, including humans, to affect changes in phenotypic consequences of gene expression.

The aim of this lecture series is:

(a) to enhance/expandyour understanding of Genetics (knowledge that was hopefully gained in Bio3900 -or its equivalent) with a more in-depth, genetic appreciation of the world,

(b) to complement this knowledge with a more molecular based understanding of classical genetic concepts, with some understanding of the technology used

and

(c) to allow you to become a little more informed than the average biologist on the topic of just how our genetics works.

 

-that is, of course, IF.... WE succeed.

To understand what has changed in Genetics over the years, you have to have a firm appreciation of "Classical Genetics". So, we will begin by quickly outlining/reviewing(?) the foundations of Classical Genetics -where and how its dictates still apply and where recent advances have modified or "nuanced" our appreciation of these accepted norms.

In this lecture series I assume/know that we have a rather mixed population of students... ranging from those who have recently taken BIOL3900 (for whom terms like linkage, test-cross, expressivity etc. are fully understood, every-day terms that esily "trip off the tongue".. and who can explain these terms at the "drop of a hat"...??) to those of you who haven't really thought of Mendel and his dividing peas for quite some time (if ever).

Thus, the novelty aspect of some of the lectures (especially the first couple) will vary from individual to individual -ranging from a review of known material to a new (hopefully more in-depth) introduction into the various, and diverse aspects of gene function, gene expression and the interaction(s) of the consequent gene products.

Nomenclature:

To pamper you all a little bit -and to clear up (hopefully) any concerns about the naming of genetic traits...

Essentially there are two predominantly used methods.

The first is the simple adoption of an initial letter, which symbolizes the genetic trait under investigation (e.g.. "H" for Huntington's disease). Then, knowing that in diploid cells there are potentially two alleles (one dominant one recessive) and defining the presence of one as a capital letter "H" (dominant allele of the trait) and the other "h" (the recessive form of the trait). Thus: "HH" = homozygous dominant , "Hh" = heterozygous , and "hh" = homozygous recessive .

This nomenclature is simple, and (to a first level of understanding) provides a quite effective appreciation of how genetic traits can effect phenotype and how they are able to be passed on from generation to generation.

A second system, however, allows for a greater variety of traits to be listed (and also gives more information as to which allele of the particular trait is normally seen in the population). This system uses the "+" sign to denote the "normal" or "wild-type" allele.

By way of an obviously absurd example...

Grass is normally green. This colour can result from the production of a variety of structures (chlorophyll springs to mind) whose synthesis is dependent upon any number of genes.  Let us assume, however, that there is only one gene that governs the colour of this particular species of grass. Now, If in a field of green grass a geneticist finds a blade of pink grass and, through a series of fundamental genetic experiments, determines that this colouration is the result of a single genetic factor she/he first needs to label the genetic trait, usually by a description of the variation in phenotype -which in this case would be its colour, green to pink.

Thus, the alleles of this particular gene would possibly be designated as "pk".

Now, the next thing the geneticist would normally do is to define whether this variation in grass colour is a dominant or a recessive trait. By undertaking a series of Mendelian crosses (which we will detail in a few minutes) it can be determined that the trait is recessive and, therefore, the lowercase "pk" is used to designate the particular "colour locus" (if the trait were dominant a capital letter could be used, "Pk").

Everyone knows that grass is not normally pink. Therefore, there must be two forms of this pink allele, the one which gives rise to the pink colour and the one which is normally present and gives rise to a green colour. Using the "+" symbol to denote the normal or wild-type allele, this allele is designated as "pk ⁺ ", with the mutant allele being given the simple "pk" symbol.

While this adoption of a modified nomenclature seems to be straight forward, it can give rise to a number of consequential interpretations of the genetic complement of cells that might not be.

Thus: "pk ⁺ / pk ⁺ " = homozygous "wild-type" (green grass), "pk ⁺ / pk" = heterozygous (green grass), because the trait is recessive), and "pk / pk" = homozygous mutant (pink grass).

If, for some reason the trait had been "DOMINANT" the different strains would be designated as..."PK⁺ / Pk ⁺ " = homozygous wild-type (which in this case would still give rise to green grass).   

Pk ⁺ / Pk" = heterozygous (which in this case would give rise to pink blades of grass, because the mutant rait is now dominant), 

Finally, "Pk / Pk" = homozygous mutant would unsurprisngly give rise to pink grass).

N.B. One cannot assume that, just because the normal (wild-type) colour of grass in any given population is green that the pink trait is "recessive". 

A classic example of this is one that we have just seen, Huntington's disease, which has three temporal variables -two of which are fatal (H⁺, H  and H, H) one gives rise to late onset and one early onset of the disease, respectively.

Having established  the nomenclature for labelling the locus that would affect the grass colour in our example, there are potentially additional, alternative variations of the gene that may replace the "+" symbol, which we will get to in a few minutes.

In addition to all these variables there are also "qualitative" differences amongst the pehnotypic effects of different mutations, which we will begin to address in a little while, and deal with more heavily at later stages in the course. These phenotypic variables differ as a consequence of the severity of the mutation on the function of a given gene -as well as potential differences in gene expression.

How did we come to appreciate the "singularity" (and duplicity [?]) of Nature (at least in our diploid world)?

It boils down to "perspectives" on the different types of GENEs and their consequences.

 

Sometimes the consequences of genetic changes give rise to major changes... gain of function vs. loss of function mutational phenotypes... one more often giving rise to dominant traits, the other -more often recessive. e.g. of a gain of function mutation could be an overactive oncogenic factor, the Ras protein.

 

   

Know how to test for Mendel's laws.