Lecture 1: Introduction: Mendelian Genetics plus
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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" is born...             2016 First "3 parent" baby is born...        Bioethical concerns abound...

genes                 genes genes          genes

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

 

     genes                                      ;           genes

 

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

 

      genes                genes           molecular tweezers

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
     

      genes


 

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 trait is now dominant), Finally, "Pk / Pk" = homozygous mutant which 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, one gives rise to late onset and one early onset of the disease.

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.

genes

 

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.

genes

Complications of interpretation also abound, and the fact that genes reside on chromosomes, and that the chromosomes come in all shapes, sizes and numbers.. (at least in plants) causes an awful lot of additional variations for inerpretation. Thankfully the majority of chromosomes per organism are usually either one or two. Even so, there are still any number of causes for genetic variation....

Penetrance The proportion of individuals in a population that manifest the genotype at the phenotypical level due to the presence of different alleles and the influence of a variety of other possible external factors that would affect their expression. eg. BRCA1 and BRCA2, their prevalence giving rise to potentially different degrees of breast cancer risk -environmental, genetic background and other factors.

Expressivity , which is the "degree" to which the genotype is expressed in the individual, due to outside influences (the number of yes/no’s coming out as maybe’s/possibly’s and probably’s in the individual?? -environmental, genetic background and other factors giving rise to subtleties of phenotype and gene expression).

a red ball

 

...but we are getting ahead of ourselves.

 

Gregor Mendel's hypotheses:

1. Hereditary determinants are of a particulate nature. Each genetic trait is governed by unit factors , which "hang around" in pairs within individual organisms.

2. When two different unit factors governing the same phenotypical trait occur in the same organism, one of the factors is dominant over the other one, which is called the recessive trait.

3. During the formation of gametes the "paired" unit factors separate or segregate randomly so that each gamete receives either one or the other of the two traits, but only one .

4. The union of one gamete from each parent to form a resultant zygote is random with respect to that particular characteristic.

 

Mendel's First Law: Two members of a gene pair segregate from each other into the gametes, whereby one half of the gametes carries one of the traits, the other half carries the other.

 

Mendel's Second Law: During gamete formation the segregation of one gene pair is independent of all other gene pairs

 

Punnett squares can easily be used to demonstrate how these factors assort themselves in the offspring.

 

-made ever more complex by a dihybrid cross.

-and even more complex by a trihybrid cross.. but with the same principles.

 

Mendel's Laws and the uses of Probability:

The product rule; two independent events occurring simultaneously is the product of each of their respective probabilities.

Roll of the di(c)e ---> 1/6 x 1/6 = 1/36. 

The sum rule; the probability of either one of two events happening is the sum of their individual probabilities.

Roll of the di(c)e ---> 1/36 + 1/36 = 1/18.

This idea gives rise to understand the probability of passing on one of the two traites...."Branch diagrams", where "R-" equals the presence of any of the "R" (or dominant) genotypes. 3/4 x 3/4 = 9/16

 

   

Know how to test for Mendel's laws.

 

While Mendel could not comprehend any of the genetic intricaies that his laws might suggest, his determination of his abstract "unitary" traits had far reaching implications in understanding inheritance of these genetic traits and how they could be inherited.

As we have discussed, each of the gene variants is termed an Allele and ALL variants of a given gene reside at a specific locus on a given chromosome.

Variation in allelic types arise by mutation or change in the DNA sequence. An allele, therefore, can arise due to a mutation at a given locus, and can be analyzed through classical genetics once that variation has been incorporated

Alleles can be randomly mutatagenized to become a different allele, depending on DNA sequence changes and maintained or lost -again in a random manner- unless acted upon by a selective pressure.

"Wild Type", as we have discussed prevously, is a term used to demonstrate the most common allele/trait of a given population. Again, being the "most common" allele in a population does not always mean that the wild-type allele will be the dominant or "superior" allele.

However, some definition of "normalcy" in the genetic expression of traits does provide an incredible advantage in the understanding of how genes work in the whole organism...

In the early twentieth century, G. H. Shull crossed two varieties of corn, and the yield went from 20 to 80 bushels per acre, thus defining a, now common, agricultural practice to increase production in plants.

This is called either hybrid vigor or heterosis, whereby crossbred strains show superior qualities, and it is a result of the fact that continued genetic "in-breeding" often leads to deleterious traits becoming "fixed" in the gene pool (an aspect we will address later). The mixing of two strains, therefore, reintroduces a number of selectible traits which can enhance the gene pool of the newly defined strains... Use of such hybridization techniques has been a common agricultural practice ever since -to increase production in crops and broadened to cattle etc...

An hypothesis called overdominance even proposes that the heterozygous condition -in certain important genes- is often considered to be selectively "superior" or have a higher fitness than the presence of either homozygote. This occurs far more frequently in cases where a single trait controls more than one phenotype. Such heterosis, however, would be slightly at odds with Mendel's idea of "independent" traits.

Even so, given the potential of heterosis, this would threaten the very crux of Mendel's ideas which are premised on the "particulate" nature of genes, and where one allele in any given gene pair is simply dominant over the other

Perhaps, Mendel wasn't perfect...

 

No, he wasn't, he was also only observing, NOT deducing. Even so, the fact that we are still talking about him is testament to how much he did get right.

 

 


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