IV.

Modern Heredity
A. Overview

B. Allelic Interactions:

C. Genic Interactions:

The effect of an allele can be influenced by other genes in the genome, at

other loci. These are called "inter"-locular effects.

1. Quantitative "polygenic" effects

There are many proteins (and RNA's) that are valuable in high concentrations;
higher concentrations than production from a single locus can produce.
Selection has favored organisms in which these genes have been duplicated
(through a process we will examine later). The organisms, with two or several
different loci that produce the same protein, can produce LOTS of that
essential molecule. A good example is r-RNA. The production of all proteins in
the cell depends on ribosomes, and they all carry r-RNA. So, selection has
strongly favored organisms that have multiple copies of the genes that encode
r-RNA; they can produce LOTS of r-RNA, and thus produce LOTS of
ribosomes... and this increases the rate that they can produce all of their
proteins. Now, for genes that encode proteins that influence a phenotypic
characteristic, multiple genes means that more than one locus produces the
protein product and influences that trait. So, the final phenotype is determined
by the cumulative, "quantitative" sum of all the genes acting on this trait.

As a consequence of many loci acting on a trait, there are many more

combinations that are possible - resulting in a wide variety of phenotypic
expression that forms a nearly 'continuous' range of variation.

For example, consider human skin pigmentation. There are at least 16 loci
that code for melanin (skin pigment) production. Although there is complete
dominance at each locus, this multiplication of genes allows for an
extraordinary and continuous amount of phenotypic variation, from all 16
genes 'on' (and very very dark skin), to 15 'on' and 1 'off' ( very dark skin), to
14 'on' and 2 'off' (a bit lighter), to , 13:3, etc. , all the way to 0 'on' and 16 'off'
(no pigments produced at all).

Humans evolved on the plains of Africa. The loss of hair was adaptive (to
decrease insulation in the subtropical heat), but this made the skin vulnerable
to UV rays that cause mutation. Selection favored humans that could make
lots of melanin, to protect the skin against these UV rays. Selection favored
humans that duplicated their melanin genes, and could thus produce more
pigment. Humans that continued to live in tropical areas continued to benefit
from this dark skin. In cooler climes with less intense sun, selection favored
humans that spent less energy on melanin production, selecting for the
recessive alleles at each of these multiple loci. In addition, lighter skinned
people benefitted at these latitudes by using the sun's energy to synthesize
vitamin D in the skin.

2. Epistasis

In epistasis, one locus has precedence over the expression at

another locus and can override it. Albinism is the classic
example. Albinism ooccurs in all populations of humans (and
many other animals). It usually does NOT involve the melanin
producing genes. (So, true albinism is NOT caused by the 0 'on',
16 'off' scenario described above). Rather, it involves another
locus. An 'aa' individual at the albinism locus does not make
the precursor for melanin. So, with no precursor from which
melanin can be made, it doesn't matter WHAT the genotypes are
at the 16 melanin loci - there won't be any melanin produced. This is why
albinism occurs in all human populations (or 'races') regardless of the skin
color typical for that population - because it is influenced by a gene that is
inherited independent of the melanin producing genes.

D. Environmental Interactions

The environment has many direct effects on the phenotype. A fox may change
from white to brown because a bucket of
white paint falls on it's head. That would be
a direct environmental effect; it happened
independently of anything going on with the
genotype. Those are NOT the effects we
are talking about here. Rather, we are
talking here about an interactive effect
between the environment and the genes at
a locus, such that the
environment changes how the genotype is
expressed as the phenotype.
1. Temperature

In arctic fox, the brown summer fur turns to white as temperatures drop. This
is NOT a direct effect of temperature change on pigment in the hair shaft.
Rather, the change in temperature changes how the genes and their protein
products work. As temperatures drop, melanin genes are turned off, or the
enzymes that catalyze the production of melanin change shape and no longer
function. The result is that no melanin is produced, and thus the fur turns
white.

2. Toxins

Susceptibility to certain mutagens will vary with the genotype. So, two people
who are homozygous for a type of lung cancer (and 'should' genetically
express that cancer) might have very different phenotypes. One, who smokes
and exposes their lungs to mutagenic compounds might trigger those cancer
genes. The other person, however, with the same genotype, might not have
cancer because they never smoked and thus never exposed themselves to
the environmental "trigger". Likewise, someone homozygous for an
alternative allele might smoke without developing lung cancer.

These effects may be "probabilistic". For instance, some genes associated

with cancers are only expressed (cause cancer) in a fraction of the individuals
with that genotype. This could be due to different environmental exposure,
but it could also be caused by different genes at other loci that interact with
this cancer gene and augment or suppress its effects through interlocular
interactions.

E. The 'Value' of an Allele

Environmental Effects: The value of an allele often depends on the

environment

In Sickle Cell Anemia, red blood cells 'sickle' when the concentration of
oxygen in the bloodstream drops. This occurs when the person is active and
the oxygen demand by muscle increases, drawing oxygen out of the
bloodstream and depressing oxygen concentration in the cells in the
bloodstream. The sickle-shaped cells do not pass through capillary beds as
easily as normal red blood cells; they clog capillaries, resulting in oxygen
deprivation and tissue damage downstream from the clot. This is usually
most pronounced in the liver, kidneys, and brain, and eventually often results
in premature death.

Sickle cell anemia is caused by an altered beta globin allele, which causes a
single amino acid change in the beta-globin proteins in hemoglobin. The trait
exhibits incomplete dominance - one "s" allele will result in some "sickling" of
red blood cells at low oxygen concentration, but the condition is not nearly as
severe as it is in the homozygous condition.

Now, you might think that even one sickle-cell allele would 'always be bad' -
after all, I just said that heterozygotes do suffer some debilitating effects. But
in this case, the "value" of a sickle cell allele - whether it is 'good' or 'bad' -
depends on the environment. In particular, it depends on the presence of
the Plasmodium parasite that causes malaria.

In the tropics, a primary source of human mortality is malaria. In 2006, nearly

900,000 people died of malaria; over 91% of these deaths were children in
Africa. There were an estimated 250 million cases reported globally. Malaria is
caused by several species of protists in the genus Plasmodium. This single-
celled parasite is transmitted by female mosquitos. When they bite a human to
take a blood meal (only female mosquitos drink blood - they use the protein to
nourish their developing eggs), the parasites enter the human host's
bloodstream and infects red blood cells. They divide mitotically, producing
hundreds of offspring and eventually rupturing the cell. Thus, infection causes
extreme loss of RBC's - "anemia" (don't get this confused with sickle cell
anemia; we are just talking about malaria right now!!). Curiously,
the Plasmodium parasite cannot reproduce in cells with the altered form of
"sickle-cell" hemoglobin - even in the heterozygous condition. So, the
heterozygote suffers some sickling on occasion, but is protected from
malaria. In Africa, SS homozygotes have lower survivorship than the Ss
heterozygotes because the SS individuals are exposed to malaria. The ss
homozygotes have lower survivorship than the Ss heterozygotes because of
the more pronounced debilitating effects of the sickle cell disease.

So, is an 's' allele "good" or "bad"? Well, that depends on other alleles at
that locus (if it's with another 's' allele it is always bad), but it also depends on
the environment. If the 's' is with an 'S' in the temperate zone, it is bad
(relative to the reproductive success of the normal SS homozygote).... but if
the 's' allele is paired with an 'S' allele in the tropics, then it is "good" - better
than having two dominant alleles (SS).
TEMPERATE ZONE: survivorship:
SS > Ss > ss

TROPICS: survivorship: SS < Ss > ss

You should relate this to the corollary of Darwin's Theory of Natural Selection.
Populations in different environments will diverge from one another
genetically, as the environment selects for different traits (genotypes).

F. Summary:

An organism is more than just the sum of their parts, even at a genetic level.
How the genotype works is not just the additive sum of all the genes acting
independently. Rather, the way some genes work depends on the other genes
in the genotype. The phenotype - what a complex organism IS - is the result of
these complex interactions between genes, with the additional layer of
environmental interactions and direct environmental effects. Indeed, given the
potential complexities involved in how 1000's of genes and a complex
environment can interact, it is rather surprising that many genetic effects are
simple enough to model as independent entities with a Punnett Square -
without considering the other genes or the environment. So, Mendelian
Genetics are actually the easiest, simplest patterns in heredity to recognize:
and that is probably why they were recognized first.

Cell Biology
I. Overview
All living things are composed of cells, so understanding how a cell works is
fundamental to understanding all living systems (this philosophical approach
is called "reductionism: figuring out how a complex system works by studying
what it is made of, and how its parts work…"). At the most simplistic level,
cells must absorb matter/energy, convert this matter/energy into a useable
form, and then use this energy and matter to make the things they need,
respond to the environment, and reproduce. Of course, these are the things
all things composed of cells must do, as well. You breathe in oxygen and you
eat food to supply your CELLS with oxygen and your CELLS with “food”. So to
understand how LIFE functions, you need to understand how cells function.
To understand the material that follows, you must know the basics of atom
structure, types of chemical bonds, the structure and properties of water, and
the types and structures of biomolecules (though we will review those as we
use them).

A. How Cells Live

Consider a new cell just produced by binary fission (bacteria and archaea) or
mitotic division (eukarya) of a pre-existing cell. This cell is roughly half the size
of the parental cell. To reach the size of the parental cell, it must grow - this
involves the synthesis of more membranes, more ribosomes, and more of all
the other components of a cell. In addition, some molecules are breaking
down and must be replaced or repaired. So, a cell has to make stuff to keep
itself alive and grow. The first law of thermodynamics states that:
"energy/matter can not created or destroyed, only transformed to other types
of matter/energy". So, for a cell to maintain itself and grow, it can't just 'create'
this new matter of membranes and ribosomes from nothing; it must take in
energy and matter and transform that energy/matter into these necessary
structures. Cells harvest energy and create new molecules through chemical
reactions - breaking molecules apart and linking their pieces together in new
combinations. These chemical reactions are catalyzed by enzymes. The
enzymes are protein molecules made by the cell, too, through other
enzymatically catalyzed chemical reactions. Enzymes are proteins. So, to
make the lipids, polysaccharides, proteins, and nucleic acids that a cell needs,
it must make the enzymes needed to synthesize these molecules. So, protein
synthesis is thus fundamental to everything else a cell does.

We can summarize cell function like this (for eukaryotic cells):

1) biological molecules are absorbed across the membrane.

2) Through chemical reactions (catalyzed by proteins called 'enzymes') in the

cytoplasm and the mitochondria, the covalent bonds in these organic
molecules are broken and some of the energy released by the breaking of
these bonds is used to add a phosphate group to ADP--> making ATP. This is
cellular respiration - transforming the energy contained in the covalent bonds
of diverse organic molecules into the energy in a weak covalent bond of a
single type of organic molecule (ATP). All enzymes can break these weak
bonds in ATP to catalyze their reactions. Photosynthetic cells can also use the
energy in sunlight to link a phosphate group to ADP--> making ATP;
converting radiant energy into chemical energy of a covalent bond. In these
two ways, cell transform energy in a diverse range of nutrients or light into one
form of chemical of energy (bonds in ATP) that can be used throughout the
cell.

3) Much of this energy is used to link amino acids together to make proteins.
These reactions occur at the ribosomes, which many be free in the cytoplasm
or bound to the endoplasmic reticulum (ER), making the ER appear fuzzy or
'rough'. Proteins synthesized by ribosomes on the rough ER are shunted into
the lumen (tube) of the ER, where they are passed to the Golgi Apparatus for
processing (changing the initial protein product into a functional protein by
cutting off some amino acids, and or binding it to another protein, fat, or
carbohydrate). Liposomes budding off from the Golgi transfer the final protein
product to the cell membrane, for incorporation in the membrane or delivery
outside the cell.

4) The sequence of amino acids in each protein is determined by the linear

sequence of nitrogenous bases in genes - regions of DNA in chromosomes.
The DNA double helix is opened, and the sequence of A,T, C, and G's is read.
Based on this sequence, a complementary sequence of RNA is synthesized.
This RNA molecule - essentially a copy of the gene - is shunted outside the
nucleus to the ribosome. It is this RNA which is "read" by the ribosome, and
determines the particular sequence of amino acids linked together into the
initial protein product. All of these steps, from uncoiling the DNA, to reading
the DNA, to making the RNA, to moving the RNA to the ribosome, the linking
amino acids together to form the protein require other specific enzymes and
energy in the form of ATP. Through this process of protein synthesis, the cell
makes the enzymes it needs to synthesize new structural and transport
proteins, new phospholipids, new polysaccharides, and new chromosomes.
Once new chromosomes are synthesized, the cell can divide into two new
cells. That's a very simple look at how cells live. It involves absorbing
matter/energy, converting that energy to a usable form, making proteins
based on the recipes in the DNA, and then reproducing. We will look at these
steps in more detail, after considering how cells divide and why.

B. Why Are Cells Small?

Cells are very small - we will see just how small in lab. But why? Well, there
are several reasons. First, chemical reactions are affected by the
concentration of reactants and their likelihood of interacting. In a small
volume, fewer molecules are needed to get a reaction to occur, and they are
more likely to interact. But another reason is this: the ratio of the volume a
cell--which represents the metabolic potential of the cell--to the surface area
of the cell--which limits the rate at which material can be provided to the
volume--changes as a cell gets larger. Consider a square cell that is one unit
of length (let say 1 micrometer) on a side. The volume is 1 x 1 x 1 = 1 cubic
micrometer. The Surface area of each side = 1 x 1 = 1 micrometer, times six
sides = 6 square micrometers in total. So, the surface area to volume ratio
(SA/V) = 6/1 = 6. As the cell grow to be 2 micrometers long, the volume
increases as a cubic function of length while the SA only increases as a
squared function of length. So, the volume = 2 x 2 x 2 = 8 cubic micrometers,
while the SA = 6 (2 x 2) = 24 squared micrometers. So, the SA/V has declined
to 24/8 = 3. So, as a cell increases in size, the volume increases faster than
the surface area, and the 'supply' of nutrients across the SA cannot keep up
with the 'demand' for nutrients by the ever-increasing volume. The metabolic
efficiency drops—and that’s the rate at which the cell can make new stuff.

Study Questions:

1. Know the difference between quantitative traits and epistatic effects - and be
able to explain the difference at a cellular (enzymatic) level.

2. Know how the environment can influence the expression of a gene; again, at
the enzymatic level.

3. Know how the environment can influence the VALUE of a trait? Relate this to
Darwin's idea of the diverge of populations in different environments.

4. Why are cells small? Explain completely in terms of SA/V ratios.