Psychology 207
Genotype and Phenotype  Jeffrey J. Wine, 11/3/99 

"It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; inheritance which is almost implied by reproduction; Variability from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms. Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved."
                                                                                Charles Darwin, The Origin of Species. 
The human genome.
What genes do.
The human genome project.
Progress in sequencing genomes.
Of what use is a genomic sequence?
Pathways from gene defects to clinical syndromes
Genotype to phenotype: mouse models of genetic diseases.
Natural animal models of human genetic diseases.
From genes to mind.
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The human genome.
A genome is all of the DNA in an organism.  The human genome consists of ~80,000-140,000 genes and ~3,000,000,000 paired nucleotides. Perhaps 95% of the DNA is non-coding, leaving perhaps 150,000,000 nucleotides for the genes, or 1500 nucleotides per gene. After subtracting non-coding regions, the average gene product would be predicted to be less than 500 amino acids in length. 

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What genes do.
Genes make proteins.  So the question becomes: what do proteins do?  Each cell of the body uses ~10-15% of the full array of genes to make ~10,000 different proteins that in aggregate enable the cell to carry out its functions.  Many proteins are expressed in every cell to perform 'housekeeping' functions such as metabolism and protein production.  Other proteins are only expressed in specific types of cells: for example rhodopsin in rods and the other color pigments in each of the respective cone cells of the retina.  The complex structure of the body and the functions to which it gives rise develops as proteins interact with each other, and with genes (proteins control gene expression) and with environmental stimuli.  

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The human genome project.
The origins of the human genome project are usually traced to a 1985 meeting on human genome sequencing held by Robert Sinsheimer at the University of California, Santa Cruz, leading Charles DeLisi and David Smith to develop plans for a Human Genome Initiative sponsored by the Department of Energy. NIH funding for human genome research began in 1987. The same year, DOE recommended a 15-year effort to map and sequence the human genome and designated a set of specialized human genome centers. The U.S. Human Genome Project formally began in October of 1990. In 1991 a genetic linkage map of the entire human genome was published, based on polymerase chain reaction/Sequence-tagged sites (PCR/STS). Spin-offs included attempts to sequence genomes of other organisms. 

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Progress in sequencing genomes.
 
  
Organism
Genome size
(megabases)
Completed
Sequence
(megabases)
% 
sequenced
Mycobacterium tuberculosis
4.4
4.4
100%
Yeast Saccharomyces cerevisiae 
12
12
100%
Nematode Caenorhabditis elegans
97
97
100%
Fruit Fly   Drosophila melanogaster essentially complete
Mouse
3,000
3
0.1%
Human
3,000
169
6%*
The entire genomes of numerous simple organisms (viruses and prokaryotic bacteria) have now been sequenced, including important bacteria such as E. coli and the influenza virus.  For more complex organisms, (prokaryotes) the first to be sequenced was common baker's yeast has been sequenced, and is available to anyone who has access to the Internet. You can search the database for any sequence of interest. The first multicellular organism, the small nematode worm C. elegans, was completely sequenced and the results published in a special issue of Science in December of 1998.  Unlike previous, single celled organisms that had been sequenced, the nematode has 302 neurons in its nervous system alone.  That may still seem a tiny number compared even with the 100,000 neurons in an animal like the crayfish, but the nematode possesses genes for most of the known molecules of vertebrate brains.

Fruits of this achievement will continue to flourish for decades to come. The yeast has ~6,000 genes, probably including representatives of most human gene families, and the nematode has, and over 19,000 genes. You might think that genes in our brains would be one set of genes not represented in these fungi, but in fact a burgeoning area of research has linked a large set of genes involved in synaptic transmission with similar genes involved in vesicular trafficking within yeast.  In any event, larger genomes are coming out faster than I can update this web page, and the entire human genome should be sequenced before you leave graduate school. 


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Of what use is a genomic sequence?
A genomic sequence will allow the rapid identification of every gene within the genome, as well as provide information on how the genes are controlled.  By comparing genomes across organisms, we can gain unprecedented insight into evolution.  For example, human and chimpanzee genomes appear to be 98.5% identical.  It has suddenly been realized that it will soon be possible to specify, exactly, what 1.5% of the genomes differ.

A huge number of genes remain to be identified, and determining the functions of the proteins they specify will occupy biologists well into the next century.  With the genomic sequence in hand, this task will proceed with enormously increased efficiency.

One of my greatest interests is individual differences in genomes, and the ways in which those differences help determine the uniqueness of every individual. 


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Pathways from gene defects to clinical syndromes.
An important special case when considering differences among genomes are those differences which eliminate the function of a protein.  In many cases this results in a 50% decrease in the   protein's function in individuals who have one defective gene, and a 100% loss of function in individuals who have two copies of the defective gene.  If a disease results from this loss, it is called a recessive genetic disease, because the defective genes are hidden and can be passed on within families for generations until, by chance, an individual is unlucky enough to obtain 2 copies of a defective gene: one copy from each parent.  It is instructive to consider how rarely this occurs.  If one person in 100 carries a defective gene for a recessive disease, only 1 person in 40,000 will be born with the disease.  If one person in 500 carries a defective gene for a recessive disease, the rarity of the disease increases dramatically: only 1 person in 1,000,000 will be born with the disease.  Thus the general rule: carriers of recessive genetics diseases are much, much more common than affected individuals.

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Genotype to phenotype: mouse models of genetic diseases.
A major outstanding question for almost all genetic diseases is to understand the pathways from defective gene to disease.  A moment's reflection makes one realize that an answer to this question usually requires deep insights into the normal function of the gene product, including all of the pleiotropic effects that occur as the gene products interact with the thousands of other products in the cell, and then cells interact within the organism.  Hence, a study of any genetic disease, tends to illuminate important general principles in biology: this is simply a special case of the general problem of relating genotype to phenotype.  That is true no matter how rare the disease, how bizarre the symptoms, and how esoteric the biochemical pathways involved.

To study pathways from genotype to phenotype, a new and powerful method has been introduced.  Cells, called embryonic stem cells, can be produced from certain strains of mice. These cells grow essentially without limit in vitro, and so millions of copies can be produced and used in experiments in which genetic methods can be used to eliminate or alter the functions of any gene in the mouse genome (provided only that its sequence is known).  Then, amazingly, entire mice can be generated from the altered cell, and with suitable breeding mice that are homozygous for the altered gene can be produced.  In this way, any recessive genetic disease for which a gene is known can be modeled in mice.

The consequences of these studies have dramatically increased our understanding of many genes, but for certain genetic diseases, mice are poor models in that they show a syndrome quite dissimilar to that observed in humans.  For many disease, in particular for neurological, psychiatric and immune system diseases, mice are poor models.  For that reason, efforts are underway to extend stem cell technology to other organisms, but so far without success. 


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Natural animal models of human genetic diseases.
My laboratory is pursuing an alternative strategy for generating animal models of genetic diseases, and more generally of illuminating how genotype contributes to phenotype.  Consider again the mathematics of recessive genetic diseases stated above:  If one individual in 500 carries a defective gene for a recessive disease, only 1 individual in 1,000,000 will be born with the disease.  The more general rule is that if carriers are present at a frequency of 1/n, affected individuals will be present at a frequency of 1/4n2. That means that for most recessive diseases, carriers could be found by sampling only a few thousand individuals, even for diseases so rare that they are considered to be "non-existent" in the population.

We are assessing the feasibility of this approach using the human genetic disease cystic fibrosis as a test case, and old world monkeys as the population.  The way in which this is being carried out will be described in class.


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A more distant goal: from genes to mind.
A common estimate is that perhaps 30% of all human genes are specific to the nervous system. Examples of such genes are those that specify rhodopsin and the visual pigments, genes that make ions channels needed for nerve impulses, and genes for myriad receptors, neurotransmitters and complex synaptic machinery. Everyone seems to be comfortable with the idea that a single mutation can change one of the visual pigments so that color vision is dramatically altered. Numerous other mutations are known to affect the retina, leading to a variety of types of color blindness, night blindness, or complete blindness. These findings are readily accepted, and can be supported by very strong evidence.

Logic suggests that other mutations will affect central processes, with consequences for virtually any psychological property. This proposition is not so readily accepted. Many reasons contribute to such skepticism. Supporting evidence is nowhere near as strong as it is for mutations that affect the retina, and the precision with which retinal mutations can be linked to visual changes is unlikely to be matched for most mutations that affect more central processes.

But there is more to it than that, and the residual resistance can be linked to the same kind of thinking that finds something demeaning in the concept that we are biological machines. We may grant machine status to the retina, but as one moves centrally, psychological defenses become more formidable.

While it is true that no link has been established between the vast majority of genes and any psychological property, that can be expected to change rapidly, and the rate of change can be expected to accelerate explosively in the coming years. How we use this new information is, in my view, one of the central issues facing modern society.

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