Molecular Genetics I. 1h 33m Robert Sapolsky video.
In order to assess sociobiology and study human behavior from another perspective, this lecture starts a deep exploration of molecular genetics. Sapolsky's approach requires no chemistry, but there is a lot of high-level detail provided.
First Sapolsky explains the central dogma of molecular biology (first espoused by Francis Crick): how genes encode RNA which encodes protein sequences which then fold into functional biological structures. Along the way we learn about a series of genes, genetic diseases, and how genes affect behavior. Then we learn that the central dogma is not true!!! Epigenetics is the regulatory system which controls gene expression often by controlling access to genes via methylation or the chromatin structure into which DNA is ensconced. A slogan might be "fertilization is all about genetics; development is all about epigenetics". Sapolsky covers many ways in which epigenetics affects behavior and disease. The new evidence about epigenetics supports the model of punctuated equilibrium first proposed by Stephen Jay Gould and Niles Eldridge.
Environment can affect DNA expression: it can regulate genetic effects. Chemical messengers can affect gene expression (e.g., hormones: blood-born chemical messengers). Pheromones regulate genes from outside chemicals. Events in the rest of the cell, organism or universe (environment) can affect gene expression. The epigenetic control system is crucial.
Protein is the structural building block of the body. Our hormones, enzymes, cell structures, etc. are mostly comprised of protein. Proteins work on the lock and key model (exception: prions): when they fit together the action happens (which may make some chemical reaction possible). So protein shape is crucial. There are 20 amino acids which are in turn the building blocks of protein. Each amino acid is more or less hydrophillic or hydrophobic (life is bathed in a water solution). The forces that these water-loving or water-hating amino acids apply cause the protein to fold into the shape that determines its function.
In the genetic code, a sequence of three (3) nucleotides (A, G, T, C, and U for RNA) codes for one amino acid. There are 4^3 = 64 possible such sequences but only 20 amino acids, so some distinct sequences code for the same amino acid. That is, some point mutations have no effect at the protein level. Even if you do get a different amino acid, depending on the function the other one may work as effectively as the original. But sometimes, the change could affect the protein behavior substantially. For example, a deletion or insertion mutation would cause a frame shift with significant consequences. It works out that about 2/3 of the time, a point mutation causes no change to protein efficacy. If we observe that more than 2/3 of the base pairs in a sequence of DNA are changed, it implies that there has been positive slection for that change. If we observe much more than 2/3 of the base pairs in a sequence of DNA are NOT changed, it implies a stabilizing or negative selection.
Sapolsky explains how you share 50% of your DNA with a sibling, but that humans share 98% of their DNA with chimps. In the 50% case, we are looking at exact gene sequences. In the 98% case, we are looking at traits which will experience a normal level of genetic drift.
Examples. Phenylketonuria (PKU) is caused by a point mutation which causes the essential amino acid phenylalanine to build up laying waste to the nervous system. Testicular-feminizing syndrome is caused by a point mutation reducing the effectiveness of the androgen (testosterone) receptor. So although the testes produce the normal amount of testosterone, female genitalia form (in some cases the male genatilia forms but results in weak sperm and in other cases the male genatilia form at puberty) and it is only when puberty fails to develop normally that your girl learns that she is really a boy (Y chromosome, no ovaries, no uterus, no menses but otherwise female). Benzodiazepines are proteins serving as chemical messengers in the brain (synthetic versions include Valium). The point mutations that affect them and their receptors affect individual differences in anxiety response. FOXP2 is a gene that has something to do with languages (2 views: coordinating motoric aspects of speech or grouping the symbolic message in language). Over the last 1/4 million years, the FOXP2 gene in humans has undergone major change. One experiment spliced the human FOXP2 gene into a mouse and the result was more complex forms of ultrasonic mouse communication.
The first chink in the central dogma was the discovery of RNA retroviruses which are enzymes that take RNA and reencode it into DNA. Another major discovery was that genes are split up between exons (those sequences that actually code for proteins) and introns (those sequences that do not express protein). Splicing at the RNA level cut out the introns and join the exons together to code for a protein. David Baltimore was the first to point out how this modular construction of genes provide the potential to encode more information: there is a combinatorial explosion in ways in which genes can be put together. The one gene one protein dogma becomes questionable. This mechanism may also explain the tissue specific expression of genes: one gene can generate all sorts of different proteins depending on the variations in splicing proteins. Then it was discovered that long stretches of DNA in between the genes is non-coding (sometimes known as "junk" DNA). In fact, 95% of DNA is non-coding! 95% can't be just packing material. We now understand that a lot of the non-coding DNA is the "instruction manual" controlling activation of genes. Transcription factors are (usually) proteins that bind to DNA "promoter" or "repressor" sequences to turn genes on or off. Chromatin is a protein that structures the DNA in the nucleus. It controls access for the transcription factors to reach the DNA. Changes to the chromatin can permanently change a gene's ability to code or not. So it provides yet another control system for gene expression. There is a regulatory system operating outside of DNA to control gene expression. So the central dogma of molecular biology (DNA -> RNA -> protein) is wrong. DNA doesn't know what it is doing: it is just a read-out under control of other systems. Most of the non-coding DNA control system is still not understood.
Examples. Androgen receptors in muscles respond to testosterone to produce the secondary sexual characteristic of larger muscles in males. The mothering style of rats will permanently affect the chromatin controlling for genes affecting stress response: those environmental changes affect the gene expression for the rest of the organisms life (some can be partially reversed). Steve Suomi at NIH has shown that in primates if you change the mothering behavior, you change the conformational access to 4000 genes! An enormous impact from environment effects.
4. Molecular Genetics I