MS130 - Biology
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Pete Markiewicz

Week 06

Web Links - Genetics

Study of genetics - how do living things pass on specific traits to their offspring? This is one of the criteria which differentiates non-living forms like fire and clouds from living things.

Examples from the popular media

Genes decide if coffee helps or hurts your heart
http://www.newscientist.com/article.ns?id=dn8816&feedId=online-news_rss20

Finger length predicts aggression in men
http://www.livescience.com/humanbiology/050203_finger_length.html

Finger length predicts sexual orientation in women
http://www.unl.edu/rhames/courses/readings/homofinger/homo_finger.html
http://www.mygenes.co.nz/finger.htm (actual data)

Mom's genetics produce gay sons (X inactivation)
http://www.livescience.com/humanbiology/060224_gay_genes.html

IDEAS OF HEREDITY - ANCIENT WORLD TO PRESENT
 

Good source
http://www.bookrags.com/sciences/genetics/history-of-genetics-ancient-and-cla-wog.html

• Inheritance based on "blood mixing"
• Preformation - animals are like Russian dolls - each sperm contains a complete individual, which in turn contains sperm with complete individuals, etc.
• Epigenesis - "organizing principle" sculpts matter into living thing.
• Aristotle (~350 BC) - one form of epigenesis - male provides "organizing principle" while female provides "unorganized matter"
• William Harvey - (1651) On the Generation of Animals - all creatures arise from an egg
• The cell theory (1830s) - all living things are made of cells, and each cell contains information needed to construct a copy of itself
• Computing model (1950s) - Discovery of DNA reveals an "informational" molecules. Cells contain "data" which is "processed" to modify nonliving matter into living structures. The processing is mechanical and logical, and very similar to digital computers.

THE DISCOVERY OF THE GENE

Gene definition
http://www.whatislife.com/gene-definition.html

Gregor Mendel - anal-retentive founder of modern genetics (science teacher)

• Some traits of living organisms are inherited in predictable ratios
• Ratios change with generation - a trait which "disappears" in the children may appear in the grandchildren
• An abstract quantum unit of inheritance - a "gene" explains the inheritance pattern
• Associated with fixed location on chromosomes in the cells - early 1900s
• Mutation by radiation or environmental insult - Morgan (this link shows inheritance of mutation, alleles)
  • Used fruit fly since lifecycle is only 14 days, has "giant" polytene chromosomes)
• Modern definition of gene - one gene specifies the structure of one polypeptide (protein subunit)
• Discovered to be composed of DNA by Watson and Crick in early 1950s
  • Genotype - the genetic data, stored in a computerlike fashion
  • Phenotype - the structure of the living organisms specified by the genotype

THE "CELL-COMPUTER" ANALOGY IN GENETICS

Industrial complex		Automated Factory		Computer hard drive		Files on hard drive		Hard drive media (magnetic/metal disk)
Animal		Cell		Chromosome		Genes		DNA molecule

Human chromosomes (roughly equivalent to hard disk partitions in computer-cell analogy)

• Normally dispersed throughout nucleus, long ribbons of DNA (about 3 feet in a human)
• "Supercoil" when time for cell division (like rubber band on model airplane)
  http://www.nanomedicine.com/NMI/ListFigures.htm
  
• More detailed structural diagrams
  http://www.cbs.dtu.dk/staff/dave/roanoke/genetics980218.html
• Chromosomes "squashed" out of the nucleus during cell division viewed under light microscope
  
• High-resolution image of human chromosome (showing supercoiled DNA strands and paternal and maternal chromatids -left and right sides) http://www.biology.lsu.edu/webfac/dpollock/4800/images/ElectronChr.jpg
  
• High-resolution image of one of the little strands sticking out from the chromosome above, showing the actual DNA strand
  
• The DNA sequence (shown in code form rather than actual DNA structure) of a small region of the chromosome DNA above, showing mutations in the data
  
• List of human chromosomes showing HOMOLOGOUS chromosomes - for each chromosome type in the cell, there is one from the father (paternal) and one from the mother (maternal). Each maternal or paternal chromosome is in turn composed of two chromatids (see below)
  
• Chromosomes carry individual genes (like data files) in defined positions in each species
• Maps of genetic diseases associated with genes on specific chromosomes
  http://embryology.med.unsw.edu.au/DNA/DNA2.htm
   
• Correspondence between human and chimpanzee chromosome, showing a small inversion (genes run in reverse order over a small distance)
  http://www.hhmi.org/news/popups/scherer_pop.html
  
• Information for genes on each human chromosome (The Human Genome)
  http://www.ornl.gov/sci/techresources/Human_Genome/launchpad/

Chromatids

• Each maternal or paternal chromosome consists of two chromatids, held together at middle by a "centromere"
   

  Chromosome from Mother	Chromosome from Father
  FOUR copies of same genetic data (with slight variations)

• Each chromatid is identical to its "sister" - it carries the same set of genes, in the same order, same sequence.
• Both chromatids come from one parent. There are two chromosomes (maternal and paternal) in each cell, bringing the number of copies of the genetic data to 4
• A cell where the chromosome has two chromatids is called "Diploid"
• Sex cells have chromosomes with only one chromatid and are called "Haploid" (sex cells)
• Similar to a RAID hard disk array (two copies of similar data on two hard drives in one computer)
  

WHAT GENES DO

• Specify the synthesis of "translated" RNAs, which are used by ribosomes to construct protein molecules with the following functions
  • Structural proteins - form physical body of cell/organism
  • Enzymes - carry out chemical reactions
  • Regulatory proteins - bind to DNA and switch genes on and off
    • Cell movements during body formation (embryogenesis)
    • Cell division rates - how fast tissue replaces itself
    • Differentiation - turn most genes off, leave a subset on (liver vs. heart cell)
    • Cell death - control number of "allowed" times a somatic/diploid body cell can divide
• Specify the synthesis of regulatory RNAs not translated to proteins, used in regulation

DIPLOID-HAPLOID

• Eukaryotic cells store genes in a linear sequence on their chromosomes.
• Normal eukaryotic cells have two copies of the same gene (like to almost identical word-processing files) - each one on a different chromosome sub-body or chromatid - the genes are alleles of each other.
• One allele comes from the paternal parent, the other from the maternal parent (each person contains a complete copy of their mother and father's genetic data
• The alleles are strung together like beads on a string - the resulting structure is called a "chromatid"
• Non-dividing cell - chromatids are "unraveled" and dispersed within the nucleus
• Two chromatids are linked together at the center during cell division, forming an "X" structure called a chromosome
• Maternal and paternal chromosomes assort differently during production of somatic (tissue) cells and gamete (sex) cells

MITOSIS

Asexual cell replication of somatic cells/tissues with diploid chromosome number
http://www.web-books.com/MoBio/Free/Ch8B.htm

• Chromosomes start with 1 chromatid
• Chromosomes make a copy of themselves - now there are two chromatids
• Chromosomes "wind up" so they are visible in the nucleus
• For a brief period, there are 4 copies of every gene in the cell
• Sister chromatids on each chromosome "grabbed" at centromere
• Pulled by "kinetichore" microtubles (mechanically)
  http://www.science.siu.edu/plant-biology/PLB117/Nickrent.Lecs/Cell.Structure.html
  
• Cell splits
• When the cell divides, each new cell gets both a maternal and paternal copy
  
• New cell has chromosomes with 1 chromatid) later makes a second chromatid copy

MEIOSIS

Replication forming sex cells with haploid chromosome number (gametes)

• Chromosomes are NOT copied, DO NOT MAKE THE SECOND CHROMATID
• Process of meiosis requires TWO cell divisions
• Meiosis Division #1
  • Homologous chromosomes (from maternal or paternal parent) align together
  • Synapsis - alignment of maternal and paternal chromosomes, total of 4 copies of data present.
  • During synapsis, copy/paste data exchange between chromatids from maternal and paternal chromosomes
  • When the cell divides, each new cell gets EITHER a maternal or paternal copy
  • The new cells get a random mix of maternal / paternal chromatids

• Meiosis Division #2
  • Like normal mitosis - sister chromatids split, go to opposite cells
  • DO NOT duplicate to re-create the second chromatid
  • Differentiate into gamete cells (eggs or sperm) in multi-celled organisms
  • These cells have ONLY ONE COPY OF EACH GENE

WHAT IS SEX? (really)

The fusion of haploid cells created by mitosis to re-form a diploid cell

• Two haploid cells fuse ("egg" and "sperm" in multi-celled organisms)
• Zygote - the fertilized egg (the moment in which all multi-celled organisms return to the original single-celled form)
• Each chromatid from finds its match, forming a new diploid chromosome
• Resulting cell ends with 2 copies of every gene, one from each starting cell (egg, sperm)
• Cell division by mitosis begins creating multi-celled organism's body (the "meat bag" protecting the gametes and getting them where they need to go)

THE PURPOSE OF SEX AND THE BODY

Greater diversity in offspring (source of "creative variation" in evolution)

• Mitosis - results in clones of parent, identical genetic data except for occasional mutations
• Meiosis-> Sex - results in all progeny (children) different from each of their parents, with a mix of traits from each
• Each "child" of sexual reproduction receives one copy of every gene one from the paternal parent and one from the maternal parent.
• One of the two copies is typically "dominant" over the other - its data is preferentially used (example with eye color)

Why sexual reproduction is favored over asexual reproduction
http://www.livescience.com/humanbiology/050330_sex_good.html

• Genes from one parent can "cancel out" bad genes from another
• "Error repair" during recombination between maternal and paternal copies of genes
• Multiple, different copies of same gene (alleles) are present - one may be better than the others some of the time
• The slight shuffling of genes produced through sexual reproduction may help organisms adapt more easily to a stressful or changing environment
• Generation - the time from when a fertilized egg begins dividing until the next fertilized egg is produced

The role of the body (somatic, diploid, non-sex cells)

• Protect the sex cells until they have a chance to do their thing
• Get them to where they need to go
• A dispensible "meat bag"
  • The body dies at the end of each generation
  • The gamete line is immortal

ORIGIN OF GENDER

• Sex can exist without defined genders
• Gender = a difference between the two gametes that fuse to form the diploid cwell
  • Isogamy - both gametes are the same size (seen in some algae)
  • Ansiogamy - one gamete is bigger than the other, produced in smaller quantity.
    • Sperm - specialization for rapid movement, dispersal (sperm)
    • Eggs - specialization for food storage (egg)
• Male and female bodies - differences in the somatic, diploid "meat bag" which facilitate propagation of the egg and sperm

HOW GENES PASS THROUGH GENERATIONS
(they do NOT blend!)

Body color (one gene, two alleles)http://curriculum.calstatela.edu/courses/builders/lessons/less/les4/casino/cas1ck.html

• Assume body color is controlled by one gene, on one chromosome with two variants
  • A = red body color
  • a =  blue body color
• Having one red color gene (Aa) creates red color (A dominates a)
• Assume mother has pure blue color (aa) genes and father has pure red color (AA) genes
• F1 generation children - All will get a red (A) and a blue (a) gene. ALL WILL BE RED IN COLOR. Shown below for a "Punnett Square"
  
   
• F2 generation children (grandchildren) - The offspring from the F1 generation mate with each other (incest, brother mates with sis sister). 1 IN 4 OF THE CHILDREN WILL HAVE A BLUE BODY COLOR
  

Skin color (two genes, two alleles)

• Assume two genes, on two different chromosomes, with multiple alleles combine to give overall skin color
• Parents are medium brown in color
• Parents carry two Genes = (A, B) both coding for melanin production, in different locations on different chromosomes
• Individual alleles may be melanin (M) or melanin minus (m)
• Assume each parent has TWO genes with FOUR alleles (two alleles per gene)
  • On first chromosome - Ma (gene 1, allele 1) PLUS ma (gene 1, allele 2)
  • On second chromosome - Mb (gene 2, allele 1) mb (gene 2, allele 2)
• The grandchildren of a black parent and white parent may have any range of color between pure white and pure black (F1 generation will be close to halfway)

INBREEDING AND ITS EFFECTS

• The practice of mating with your parent, sister, brother
• Often used to domesticate plants, create new domestic animal breeds
• Tends to "concentrate" one gene allele at the expense of others - offspring become more and more identical to parents over time
• Tends to CONCENTRATE genetic defects
•  Runs counter to our notions of "pure" types - mongrels are more genetically diverse AND genetically superior to purebreds

Most Ashkenazi Jews descended from only four women (which is why they have so many genetic diseases)
http://www.livescience.com/history/ap_060112_jew_history.html

SEX-LINKED GENETIC TRAITS

• The chromosomes that determine sex are not identical (X and Y)
  http://fig.cox.miami.edu/~cmallery/150/mendel/Ychromosome.htm
• The Y chromosome has almost no genes
• The X chromosome is the largest chromosome in the cell (most genes)
  
• The role of the Y chromosome is to suppress some genes on the X chromosome to create a male.
• Y evolved from an X-like chromosome about 300 million years ago (divergence of mammals and birds/dinosaurs)
  http://www.abc.net.au/science/news/stories/s63100.htm
• Modern birds have the opposite system from mammals - a small Y-like chromosome in females, two X-like chromosomes in males

Inheritance of sex-linked traits (shown for a Punnett Square)

• Males can only inherit their "X" chromosome from their mothers - so they're more like their mothers than fathers
• Females inherit one "X" chromosome from their mother and one from their father - so they're slightly more like their fathers than males are.
• Females get two copies of X, while males get one copy of X and one copy of Y
• In females, a defective gene inherited from one parent on the X chromosome, is usually "buffered" by the corresponding allele on the X chromosome inherited from the other parent
• In males, any defective genes on the X chromosome are NOT buffered - so males show a higher incidence of genetic disease.
• Examples of X-linked traits
  • Haemophilia
  • Absence of sweat glands
  • Skin/coat color (in cats)
  • Color blindness
  • Intelligence?

ADDITIONAL SOURCES OF GENETIC VARIABILITY

• Recombination - while paired, the paternal and maternal chromatids may exchange pieces back and forth (like parts of files copied/pasted between each other)
• Mutation - change in DNA caused by environmental insult or "error" in copying proteins (like a defective hard drive disk head writing bad data to a disk)

GENETIC COUNSELING

• Using classic genetics, a counselor can calculate probability of a genetic defect appearing in children
• DNA tests allow direct identification of additional dangerous traits

BIOTECHNOLOGY

Using knowledge of genetics, plus the structure of DNA, RNA, proteins (see week 01) to manipulate living organisms like machines.

Genetic engineering - Modifying the DNA to put desired genes into an organism

• Methods
  • Selective breeding (artificial evolution) - Use normal sexual reproduction, select some offspring, destroy the others (culling)
    Like deliberately copying computer data with errors to many hard drives, saving only the hard drives with file changes you like

  • "Naturally" Mutant Cats (only survive because humans like them)
    http://www.messybeast.com/poly-cats.html

  • Direct manipulation - modify code in DNA by chemical means, replace  unaltered code with altered code of DNA molecule synthesized in laboratory. Like making the genome "write enabled" and copy/pasting data into files on a hard disk.
    • Methods - Use viruses that "naturally" insert DNA, RNA into cells (adenoviruses, retroviruses)
      
• Applications
  • "Improved" plants and animals
    • "Golden rice" - Rice producing crucial vitamin A
      http://www.colostate.edu/programs/lifesciences/TransgenicCrops/hotrice.html
    • Crops that are resistant to insects, herbicides (e.g. produce insect poisons)
      http://www.ers.usda.gov/publications/aer786/
    • Genetic engineering of crops creates "superweed"
      http://www.guardian.co.uk/gmdebate/Story/0,2763,1535428,00.html#article_continue
    • Genetically-engineering flowers to recover lost scents (bred out when flowers made brighter, more colorful, by selective breeders over the centuries)
      http://www.sciencenews.org/articles/20050924/bob10.asp
    • Cats with no allergen proteins (inactivate gene producing Fel D1 protein)
      http://www.webmd.com/content/article/96/103591.htm
      Allerca "lifestyle" pets - http://www.allerca.com/
    • Fish that glow in the dark (luminescent jellyfish protein inserted into their DNA)
      http://www.glofish.com/
    • Concerns
      • Cryptic toxic effects on food, environment
      • Reduction of bio-diversity
      • Political power shift - agriculture becomes (even more) of an industry
  • Gene therapy - replace defective genes in humans with a "good" copy
    • Adding blood-clotting protein to DNA of hemophiliacs
    • Changing high-cholesterol gene to low-cholesterol version
    • Putting the correct protein into cystic fibrosis patients
    • Adding back the right muscle gene for muscular dystrophy patients
    • Putting in the right haemoglobin protein in sickle-cell anemia patients
    • "Weismann Barrier" - make sure that genetic changes ONLY affect diploid somatic cells, NOT haploid sex cells
  • Cloning - Make a genetically identical twin of an existing organism
    • Method - "trick" a diploid cell into thinking it is two haploid sex cells which just fused  to make a game - it will then divide like a fertilized egg.
    • Organism is exactly the same as a "natural" identical twin
    • Does not inherit memories, etc (Hollywood crap)
    • A "clone army" would be WEAKER (less genetic diversity) than a regular army - so George Lucas should take this class!
  • Stem cells - "Trick" undifferentiated diploid cells into thinking they are part of the early embryo (rather than the fertilized egg) so they differentiate to become a specified kind of tissue. Use this to regenerate tissues in old people
  • DNA testing
    • Read the exact code of small regions of human DNA
    • Trace amounts of DNA (billionths of an ounce, one human hair, fingerprint) are sufficient
    • Comparing sequences determines the probability that a sample comes from an individual person
    • Typical tests can rule out whether or not an individual could be the source of a DNA sample - one in 50 billion, 100 billion, or even more
    • Society problem - lawyers can "pitch" genetic nonsense to untrained jurors who don't understand the scientific method ("reasonable doubt" versus scientific likelihood)

     

• Protein engineering - Modifying the "molecular machines" so they carry out chemical reactions
  • Methods
    • Genetic engineering - direct manipulation of DNA sequences
  • Applications
    • Industrial - bacteria "eating" toxic waste, digestive enzymes that are stable in laundry detergent
    • Nutrition - make enzymes more efficient, increase photosynthesis efficiency
    • Health - bacteria producing human proteins (e.g. blood-clotting protein for hemophiliacs)

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