1 Nature vs. Nurture-4 What makes us human?Nurturist position: Beyond Human Nature by Jesse J. Prinz -- Norton Fall 2016 D.D. Reeder

2 DNA DNA is a linear chain of base pairs (4) linked to an inert backbone Chromosomes are packaged DNA All 23 in nuclei of all cells (except hemoglobin) Histones Information is contained in punctuated sequences of these base pairs For a short time in the 20th century, it was revealed truth that all inherited information was contained in the DNA. So we were looking for a gene for everything. DNA is the information passed down through the germ cells and provide a “blueprint, recipe…” for the proteins used in the development of the organism. Even then this picture was more complicated – for example, the amino acids that the template collects to form the protein are often not all available inside the nucleus with the DNA. RNA used to carry the information outside the membrane to build the protein. RNA splicing can carry information from different parts of the DNA molecule and perhaps more strangely, from two different chromosomes! Noncoding DNA, once thought to be junk left over from evolutionary attempts to change, was thought to be about 80% of DNA. Now we have identified other functions for this material—promoter, operator, terminator, inon to the telemeres. Intermediate structure is very important – DNA cannot be used as a template when wrapped around the histones. A Gene is the sub-sequence needed to build a protein (combination of amino acids) Fall 2016 D.D. Reeder

3 Repair Errors/damage frequent Need correction/repairExternal damage or during mytosis Despite complexity and the considerable energy required all multicelled creatures have such a repair mechanism Not 100% effective All multicelled organisms have DNA repair (as well as cell replacement or repair) Significant energy is allotted to repair Just one double-strand break could require >10,000 ATP molecules Cells with mutations in one strand only (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous because they can lead to genome rearrangements. Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. In a typical repair the enzyme removes a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. Some mutations occasionally create new genes from previously noncoding DNA. Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae (a subclass containing humans and gorillas) two chromosomes fused to produce human chromosome 2; this fusion did not occur in the other apes, and they retain these separate chromosomes. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations. One indication that DNA damages are a major problem for life is that DNA repair processes, to cope with ubiquitously occurring DNA damages, have been found in all cellular organisms in which DNA repair has been investigated. For example, in bacteria, a regulatory network aimed at repairing DNA damages (called the SOS response in Escherichia coli) has been found in many bacterial species. E. coli RecA, a key enzyme in the SOS response pathway, is the defining member of a ubiquitous class of DNA strand-exchange proteins that are essential for homologous recombination, a pathway that maintains genomic integrity by repairing broken DNA. Genes homologous to RecA and to other central genes in the SOS response pathway are found in almost all the bacterial genomes sequenced to date, covering a large number of phyla, suggesting both an ancient origin and a widespread occurrence of recombinational repair of DNA damage. Eukaryotic recombinases that are homologues of RecA are also widespread in eukaryotic organisms. For example, in fission yeast and humans, irreploicable cells human One double strand break is estimated to require >10K ATP to repair –used in signaling the presence of the damage, the generation of repair foci, and the formation (in humans) of the repair molecules. Still may not be successful and lead to apoptosis Spring 16 PLATO

4 Mutation DANGER! DNA is templateChange in the sequence can be passed to the next generation Replication sequential errors Damage abnormal chemical structure Point defects Single strand breaks Double strand breaks Spontaneous (chance) Induced (external to DNA) Cells with mutations in one strand only can function normally with the unmutated version until the good copy fails. Point mutations may occur during DNA replication. Other mutations are physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Double-strand breaks are particularly hazardous to the cell because they can often lead to irreparable genome rearrangements. A major failure can lead to the death of the cell. Some types of mutation occasionally create new genes from previously noncoding DNA. Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae (a subclass containing humans and gorillas) two chromosomes fused to produce human chromosome 2; this fusion did not occur in the other apes, and they retain these separate chromosomes. These affect evolution by preserving genetic differences between these populations. DNA damage and mutation have different biological consequences. Because the metabolic material in the cell can cause damage, the ovum is protected by moving all this stuff outside and use supplementary cells to nourish it. DNA damages accumulate in non-replicating cells, such as cells in the brains or muscles of adult mammals and can cause aging. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention Some cells, such as skin cells, divide and reproduce quickly. Other cells, such as certain nerve cells, do not divide or reproduce except under unusual circumstances. Accululation results in aging. >10,000 errors per cell per day (humans) DANGER! Germ cell heritable Somatic aging cancer? Fall 2016 D.D. Reeder

5 Is that all there is? Awesome (unnecessary?) Complexitymany enzymes needed duplicate DNA (only 1 used) make tRNA and mRNA (signaling example) make the proteins needed in the cell (often outside membrane) …....!! Cell differentiation Since the complete DNA templates is present in every cell (almost), then how are the different cells possible? Stem cells (pluripotent) Red blood cells (no DNA) Muscle cells (need energy) Nerve cells (no replication) Liver (skin) cells (regeneration) Environment is necessary -- other enzymes 4 divisions into identical cells (embryonic stem cells) before finding a temporary home in the placenta. Also possible to reverse the differentiation and make “adult” stem cells (pluripotent) Dolly was made this way!? Fall 2016 D.D. Reeder

6 What else? Gene Expression and/or Gene RegulationIf the DNA were the whole story, variation (phenotypes) could only result from mutation even so since there are two copies of each gene (two parents) only one is useful as a template -- Who chooses? How? Gene Expression and/or Gene Regulation Specific functionality different for different cell-types Vastly different time scales (adrenalin – insulin -….) genes are non-deterministic that is not by themselves. Environment is necessary ** Differentiation (specialization), gene expression and regulation are all aspects of the same phenomena. “Multicellular organisms depend on the precise orchestration of gene expression to direct embryonic development and to maintain tissue homeostasis through their life spans. Exactly how such cell type–specific patterns of gene expression are established, maintained, and passed on to the next generation is one of the most fundamental questions of biology.* Honeybees How diet (environment) + genes affects development. Major dysfunction – cell death Minor dysfunction – phenotyping Malfunction – aka disease (cancer, diabetes? auto immune?...) Fall 2016 D.D. Reeder