Chapter 14 Human Heredity 1/30

14.1 Human Chromosomes What makes us human? –We must explore genetic instructions in individuals –Our cells are very similar to animal cells –Genome = full set of genetic info that an organism has in its DNA = the study of any genome starts w chromosomes -chromosomes: bundles of DNA & protein in nuclei of euk cells 2/30 Human cartilageChicken cartilage

14.1 Human Chromosomes (continued) Karyotype = displays complete diploid set of chromosomes arranged in pairs, in order of decreasing size –Taken during mitosis Pic displays a human cell w/23 chromosome pairs 3/30

14.1 Human Chromosomes (continued) Humans have 46 c’somes –23 from Mom, 23 from Dad –2 of 46 = sex c’somes, they determine it! Women= XX Men= XY –44 of the 46 are autosomal c’somes (autosomes) 4/30

14.1 Human Chromosomes (continued) –All human egg cells carry a single X c’some –Half of all sperm cells carry an X c’some and half carry a Y c’some Why male:female birth ratio is about 50/50 –X chromosome carries >1200 genes –Y is much smaller carrying only ~140 genes Most associated with male sex determination and sperm development 5/30

14.1 Human Chromosomes (continued) Human genes follow Mendel’s principles & inheritance patterns, like other organisms Many human traits follow dominance patterns –Ex. MC1R gene w skin & hair color. Two recessive alleles=red hair, dominant alleles=darker hair color –Ex. Rheus (Rh) factors + is dominant Human gene alleles show codominant inheritance and multiple alleles. –Ex. ABO blood group, black and white chicken, bunny’s coat color 6/30

14.1 Human Chromosome (continued) –Blood Group Genes –ABO blood group - 3 alleles for this gene (I A, I B, i) The 3 alleles produce antigens on surface of RBCs I A and I B are codominant (like the speckled chicken) i is recessive (ii= no antigen, blood type O) –Rh (Rhesus) is determined by a single gene Rh + is dominant Rh - is recessive 7/30

14.1 Human Chromosome (continued) Genotype Phenotype – Genotype I A I B I A I A I A I i AB – I A and I B A – I A and I A, I A and I i iiI B I B I i O – iiB – I B and I B, I B and I i 8/30 + -

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14.1 Human Chromosome (continued) Sex-Linked Inheritance –Certain genes are found on sex (X and Y) c’somes, they are sex-linked genes. –Since Y c’somes are only in males, Y c’some genes are passed directly from father to son. –Since men have only one X c’some, they sometimes have certain issues, such as color vision… 10/30

14.1 Human Chromosome (continued) Sex-Linked Inheritance (continued) –Color Vision The x c’some has 3 genes responsible for color v. –Any allele defect in an X c’some can cause this esp for men Girls have two X c’somes, so less chance of problems b/c if they get that defective, recessive gene from one parent, they most likely have a normal, dominant gene from the other parent. More color blind boys because they only inherit 1X and that is from Mom. If she is color blind, her son will definitely be too. 11/30

What do YOU see? (Tests for color blindness)

14.1 Human Chromosome (continued) X-Chromosome Inactivation –Since boys have 1 X c’some, how do girls adjust to having an extra? –In females, most of the genes in one of the X c’some are randomly switched off, forming a dense region in the nucleus called the Barr body, which is usually not found in a male chromosome » » Neat fact: FEMALE calico cats are tri-colored. Spots of fur controlled by a gene on the X. Spots are either orange or black, depending on which X is inactivated! 13/30 Click here for Mr Anderson X Inactivation

14.1 Human Chromosome (continued) Pedigree chart (p 397) shows family relationships –Helps show if a trait is inherited –Determines whether a trait is caused by dom/rec allele & whether gene is auto or sex-linked Pedigree analysis makes it possible to determine the nature of genes & alleles assoc w inherited human traits –Genetic counselors use it to determine family member genotypes are males and O are females Shaded means trait is expressed Not shaded means trait is not expressed (but they may carry the genes for the trait) 14/30

14.2 Human Genetic Disorders Genotype & phenotype (organisms characteristics) are directly linked –Changes in DNA sequence changes proteins –Ex. Ear wax (p. 398) Genetic disorders -> caused by gene changes Changes in a gene’s DNA sequence = changed proteins & altered phenotype –Sickle-Cell Disease –Huntington’s Disease –Cystic Fibrosis 15/30

14.2 Human Genetic Disorders (continued) Sickle Cell –Mistake in hemoglobin the protein in RBCs that carries O 2 The mistake makes hemoglobin sticky, less soluble& a sickle shape - molecules clump into long fibers, forcing cells into a sickle shape -Sickle Cells are more rigid than normal blood cells (get stuck in capillaries) 16/30

Cystic Fibrosis –Caused by the deletion of 3 bases for a protein (CFTR). Protein folds improperly & malfunctions –People w/1 normal copy of CFTR are unaffected –People with two copies of this allele will have Cystic Fibrosis. -causes digestive issues, excess mucus, and clogged passageways. 17/ Human Genetic Disorders (continued)

Huntington’s Disease –Caused by dominant allele for a protein in brain cells –Codon CAG repeats a lot. It codes for glutamine. The more repeats, the earlier the disease shows and more severe symptoms are. Shows up later in life. -Why this causes disease is still unknown –Progressive loss of muscle control & mental function until death 18/ Human Genetic Disorders (continued)

Genetic Advantages –How are Sickle Cell & CF common if they are fatal to their carriers? –Sometimes having a recessive allele for these disorders can benefit a person. Sickle cell is helpful for people who live where malaria (a parasitic disease) is present. Heterozygous people (for sickle cell) are healthy. When their oxygen levels decrease, the cells become sickle shape and the body destroys the misshapen cell as well as the parasite. 19/ Human Genetic Disorders (continued)

Chromosomal Disorders –C’somes usually separate in meiosis, but sometimes something goes wrong. –Common error -> when homologous c’somes fail to separate = NONDISJUNCTION –If this occurs, abnormal # of c’somes may go into gametes (a disorder may result) Ex. A trisomy, Turner’s syndrome, Klinefelter’s syndrome (p. 401) 20/ Human Genetic Disorders (continued) Click here for an article about the Oldest Case of Downs Syndrome

Chromosomal Disorders (continued) –Nondisjunction of sex chromosomes can occur Turner’s Syndrome – only one X –Causes women to be sterile 21/ Human Genetic Disorders (continued) Linda Hunt

Chromosomal Disorders (continued) –Nondisjunction of sex chromosomes can occur Klinefelter’s Syndrome XXY –There have been cases of XXXY and XXXXY –Interferes with reproduction 21/ Human Genetic Disorders (continued)

14.3 Studying the Human Genome After discovering the genetic code, scientists wanted to read it. DNA is a large molecule, even the smallest human chromosome has 50 mil base pairs. Hard to read! We now have tools to help us. –The tools help cut, separate, and read DNA base by base 22/30

14.3 Studying the Human Genome (continued) Cutting –Nucleic acids: different from other macromolecules Makes DNA easy to extract from cells & tissues –Restriction enzymes cut DNA into sm pieces called restriction fragments – Different enzymes cut at diff nucleotide sequences/points. 23/30

Separating –Once cut, gel electrophoresis separates DNA fragments allowing scientists to analyze it GE: Put DNA frags at one end of a “porous” gel, an electric voltage is applied to gel. The (negatively charged) DNA moves to the positive end of the gel –DNA size affects the speed and length it travels –Result = pattern of bands, DNA binds to stains & they become visible 24/ Studying the Human Genome (continued)

Reading –After separating, DNA fragments are read w/a special “trick” –Single stranded DNA is put into a test tube w/ DNA polymerase ATCG also added, some have dyes on them When a dyed ATCG is added to the DNA fragment (by DNA polymerase) the synthesis of the second side of DNA stops. Pieces run through gel electrophoresis and the order of colored bands on the gel tells the exact sequence of DNA bases 25/ Studying the Human Genome (continued)

The Human Genome Project –13 yr international effort to sequence all 3 billion base pairs of human DNA & ID all human genes Other goals: sequence model organism’s genomes to interpret human DNA, develop technology, explore gene functions, study human variation, train future scientists. Sequencing and Identifying Genes –Today most of the data is used to find genes by looking for promoters –“shotgun sequencing” -cutting DNA into random frags & determining base seq for each frag. Use computers to put frags together 26/ Studying the Human Genome (continued)

Comparing Sequences –Most (not all) of our DNA is identical when compared person to person! One base in 1200 will differ –These are called SNPs (single nucleotide polymorphisms) –There are certain sets of closely linked SNPs, called haplotypes Makes sense as we are human. We all have to make hemoglobin, insulin, growth hormone, etc. That small difference makes us all look different! 27/30 Click here for Mr Anderson DNA Fingerprinting 14.3 Studying the Human Genome (continued)

What we learned… –The human genome in haploid form contains 3 billion nucleotide bases –Only ~ 2% of our genome codes for proteins –C’somes contain large areas w/very few genes –Human Genome Proj found genes & associated particular sequences in them w/diseases/disorders –Our genome - very similar to other organism’s genomes including fruit flies, worms, and yeast 28/ Studying the Human Genome (continued)

Project data may help us find DNA sequences associated w/diabetes, cancer, other health problems Also transferred impt new technologies to the private sector (incl agriculture & med) Catalyzed US biotech industry & fostered development of new med apps 29/ Studying the Human Genome (continued)

New Questions –Ethical, legal, social issues w/DNA data availability –Privacy?! Who should be able to see/use this data? President George Bush signed the Genetic Info Non- discrimination Act prohibiting insurance companies/ employers from discriminating based on genetic test results 30/ Studying the Human Genome (continued)

Fugates of Kentucky: Skin Bluer than Lake Louise By SUSAN DONALDSON JAMES Feb. 22, 2012— go.com Benjamin "Benjy" Stacy so frightened maternity doctors with the color of his skin -- "as Blue as Lake Louise" – that he was rushed just hours after his birth in 1975 to University of Kentucky Medical Center. As a transfusion was being readied, the baby's grandmother suggested to doctors that he looked like the "blue Fugates of Troublesome Creek." Relatives described the boy's great-grandmother Luna Fugate as "blue all over," and "the bluest woman I ever saw.“ In an unusual story that involves both genetics and geography, an entire family from isolated Appalachia was tinged blue. Their ancestral line began six generations earlier with a French orphan, Martin Fugate, who settled in Eastern Kentucky. Doctors don't see much of the rare blood disorder today, because mountain people have dispersed and the family gene pool is much more diverse. But the Fugates' story still offers a window into a medical mystery that was solved through modern genetics and the sleuth-like energy of Dr. Madison Cawein III, a hematologist at the University of Kentucky's Lexington Medical Clinic. Cawein died in 1985, but his family charts and blood samples led to a sharper understanding of the recessive diseases that only surface if both parents carry a defective gene.

The most detailed account, "Blue People of Troublesome Creek," was published in 1982 by the University of Indiana's Cathy Trost, who described Benjy's skin as "almost purple.“ The Fugate progeny had a genetic condition called methemoglobinemia, which was passed down through a recessive gene and blossomed through intermarriage. "It's a fascinating story," said Dr. Ayalew Tefferi, a hematologist from Minnesota's Mayo Clinic. "It also exemplifies the intersection between disease and society, and the danger of misinformation and stigmatization.“ Methemoglobinemia is a blood disorder in which an abnormal amount of methemoglobin -- a form of hemoglobin -- is produced, according to the National Institutes for Health. Hemoglobin is responsible for distributing oxygen to the body and without oxygen, the heart, brain and muscles can die. In methemoglobinemia, the hemoglobin is unable to carry oxygen and it also makes it difficult for unaffected hemoglobin to release oxygen effectively to body tissues. Patients' lips are purple, the skin looks blue and the blood is "chocolate colored" because it is not oxygenated, according to Tefferi. "You almost never see a patient with it today," he said. "It's a disease that one learns about in medical school and it is infrequent enough to be on every exam in hematology.“ The disorder can be inherited, as was the case with the Fugate family, or caused by exposure to certain drugs and chemicals such as anesthetic drugs like benzocaine and xylocaine. The carcinogen benzene and nitrites used as meat additives can also be culprits, as well as certain antibiotics, including dapsone and chloroquine.

The genetic form of methemoglobinemia is caused by one of several genetic defects, according to Tefferi. The Fugates probably had a deficiency in the enzyme called cytochrome-b5 methemoglobin reductase, which is responsible for recessive congenital methemoglobinemia. Normally, people have less than about 1 percent of methemoglobin, a type of hemoglobin that is altered by being oxidized so is useless in carrying oxygen in the blood. When those levels rise to greater than 20 percent, heart abnormalities and seizures and even death can occur. But at levels of between 10 and 20 percent a person can develop blue skin without any other symptoms. Most of blue Fugates never suffered any health effects and lived into their 80s and 90s. "If you are between 1 percent and 10 percent, no one knows you have an abnormal level and this might be the case in a lot of unsuspecting patients," he said. Many other recessive gene diseases, such as sickle cell anemia, Tay Sachs and cystic fibrosis can be lethal, he said. "If I carry a bad recessive gene with a rare abnormality and married, the child probably wouldn't be sick, because it's very rare to meet another person with the [same] bad gene and the most frequent cause therefore is in-breeding,“ Tefferi said. Such was the case with the Fugates. Martin Fugate came to Troublesome Creek from France in 1820 and family folklore says he was blue. He married Elizabeth Smith, who also carried the recessive gene. Of their seven children, four were reported to be blue. There were no railroads and few roads outside the region, so the community remained small and isolated. The Fugates married other Fugate cousins and families who lived nearby, with names like Combs, Smith, Ritchie and Stacy. Benjy's father, Alva Stacy showed Trost his family tree and remarked, "If you'll notice -- I'm kin to myself,“ according to Trost. One of Martin and Elizabeth Fugate's blue boys, Zachariah, married his mother's sister. One of their sons, Levy, married a Ritchie girl and had eight children, one of them Luna. Luna married John E. Stacy and they had 13 children. Benjy descended from the Stacy line.

Modern Fugates Still in Kentucky - ABCNews.com was unable to determine if Benjamin Stacy is still alive -- he would be 37 today. Trost writes that he eventually lost the blue tint to his skin, but as a child his lips and fingernails still got blue when he was angry or cold. His mother Hilda Stacy, who is 56, appears to still live in Hazard, Ky., but did not answer calls to her home. Other relatives are scattered throughout Virginia and Arkansas. Most of what scientists know about the family was discovered by Cawein, the grandson of Kentucky's poet laureate, who had done pioneering research on L-dopa as a treatment for Parkinson's disease. Later in 1965 he was famous for another reason. His wife was murdered by chemical poisoning, but no one was ever indicted. Cawein heard rumors about the Fugates while working at his Lexington clinic and set off "tromping around the hills looking for blue people," according to Trost's account. At an American Heart Association clinic in the town of Hazard, Cawein found a nurse, Ruth Pendergrass, and she was willing to assist. She remembered a dark blue woman who had come to the county health department on a frigid afternoon seeking a blood test. "Her face and her fingernails were almost indigo blue," she told Trost. "It like scared me to death. She looked like she was having a heart attack. I just knew that patient was going to die right there in the health department, but she wasn't a'tall alarmed. She told me that her family was the blue Combses who lived up on Ball Creek. She was a sister to one of the Fugate women.“

More families were found -- Luke Combs, and Patrick and Rachel Ritchie, who were "bluer'n hell" and embarrassed by their skin color. Cawein and Pendergrass began to ask questions -- "Do you have any relatives who are blue?" -- and mapped a family tree and took blood samples. The doctor suspected methemoglobinemia and uncovered a 1960 report in the Journal of Clinical Investigation. Dr. E. M. Scott, who worked in public health at the Arctic Research Center in Anchorage, had seen a recessive genetic trait among Alaskans that turned their skin blue. That suggested an inbred line that had been passed from generation to generation. To get the disorder, a person would have to inherit two genes -- one from each parent. When both parents have the trait, their children have a 25 percent chance of getting the disorder. Scott speculated these people lacked the enzyme diaphorase in their red blood cells. Normally diaphorase converts methemoglobin back to hemoglobin. All of the blue Fugates he tested had the enzyme deficiency, just like the Alaskans Scott had observed. Their blood had accumulated so much of the blue molecule that it over-powered the red hemoglobin that normally turns skin pink in most Caucasians. The bluest of the bunch was Luna, and she lived a healthy life, bearing 13 children before she died at the age of 84. As coal mining arrived in Kentucky in 1912 and the Fugates moved outside of Troublesome Creek, the blue people began to disappear. Doctors say Benjy likely carried only one gene for methemoglobinemia, because he eventually had normal skin tones, and the likelihood of him marrying a woman with the same recessive gene would have been small. By the time reports appeared in the media on the disorder, the Stacy family was upset with insinuations about in- breeding that fed into stereotypes of backwoods Appalachia. "There was a pain not seen in lab tests," wrote Trost. "That was the pain of being blue in a world that is mostly shades of white to black.”