Human Bio 4: Pedigrees – Flashcards

Much of what we have learned about patterns of inheritance has been derived from experiment either with "domestic" or "lab" organisms. However, gathering information on certain traits or from some organisms (e.g. humans) by experiment is neither practical nor ethical. To analyze such questions scientists turned to breeding records i.e. the "pedigree" of animals or genealogical records for humans. GENETIC PEDIGREE ANALYSIS, however, is somewhat more elaborate than a simple "family line" genealogy. Here, in addition to direct line (e.g. father to son/daughter) multiple relatives and even "in-laws" may be included. In addition, relevant information on the PHENOTYPE of the individuals is also included

1) To determine whether an observed trait is indeed inherited vs. environmentally determined. 2) To explain the "mode of inheritance" of the allele of a given gene - dominant or recessive, autosomal or recessive. 3) Once the mode is understood, to council parents on the probability or "risk" of passing on a given trait. 4) As a "Gene Hunting" technique - i.e. is some newly discovered trait inherited "along with" some known characteristic. Since the technique is time consuming and relatively complicated it is usually performed only on "significant" traits. In practice this means genes causing disease or clear physical abnormalities rather than "cosmetic" characteristics

In order to communicate effectively with one another Geneticists created a "standard" set of symbols by which they present a pedigree. This includes; squares for males, circles for females, filled symbols for affected individuals etc. However, collecting accurate information with which to fill in their chart can be a considerable challenge. a) Actual written records over several generations of a family are fairly rare. b) The "affected" family's knowledge of distant (in time, space or relationship) relatives is likely to be incomplete or only partially accurate. c) Living relatives may be widely scattered about the country or world making verification and/or expansion of the family "database" difficult. d) The information or "recollections" that are provided may be hazy, or exaggerated/understated for personal reasons. e) The phenotypic expression of the trait under study may itself vary. This can make assignment of an individual to the affected vs. non-affected category ambiguous. Such variation can occur due to differences in 1) the mutant allele, 2) the genetic "background" or 3) the environmental conditions

Autosomal Dominant genetic defect, gets in blood vessels and stink, it can cut off blood flow and can lead to a heart attack (25% more frequent) -cholesterol should be below 190, heterozygous infants have twice this level *defect in LDL (1 in 500), needs a carrier in the blood (LDL carrier protein) -use an LDL receptor, if too much cholesterol is intaked, not enough receptors, so not everything can be processed, excess builds up homozygous: has 0 receptors to process cholesterol heart/liver transplants: moderately successful, drug treatment and low diet can help heterozygous and normal "overeaters"

1) As a practical matter pedigree analysis is most effective for traits that are controlled in a mendelian fashion by a single gene. If a characteristic is controlled by more than one gene pedigree analysis may suggest that but it will be difficult to unravel the "mode of inheritance" of these genes simultaneously. 2) Methodologically, a geneticist will take the initial information provided by the family and (assuming single gene inheritance) will propose a hypothesis as to its mode of inheritance. He/she will then collect more family data to support or refute the hypothesis. 3) A single or small pedigree may be sufficient to rule out certain modes of inheritance but may not be able to limit the possibilities to just one. 4) Usually multiple pedigrees carried out by different geneticists on different affected families is required to "prove" and "confirm" the mode of inheritance for a given genetic disease. Despite these difficulties, from 1900 to 2000 some 4500 human traits have been at least preliminarily analyzed and shown to display Mendelian inheritance. These now have been subdivided into a few broad categories; AUTOSOMAL DOMINANT, AUTOSOMAL RECESSIVE, X-LINKED DOMINANT, X-LINKED RECESSIVE, Y-LINKED and MITOCHONDRIAL

We will now describe some of the principles and findings of Human Pedigree Analysis. We will, however, proceed in a somewhat historically backwards fashion - first presenting the conclusions of the study as to mode of inheritance, then describing the data and principles that lead to the conclusion and finally describing some of the diseases that were the starting point of the investigation

1) Individuals have at least one affected parent. Dominant traits are expressed. 2) MALES AND FEMALES ARE EFFECTED IN ABOUT EQUAL NUMBERS. Therefore sex linkage is unlikely. 3) BOTH MALES AND FEMALES TRANSMIT THE TRAIT. Male to male transmission rules out X-linkage. 4) MOST AFFECTED INDIVIDUALS ARE HETERROZYGOUS. A finding of heterozygosity in and affected individual indicates the trait is dominant. Heterozygosity is indicated when 50% of the offspring of the union of an affected with a normal individual are affected. 5) TWO AFFECTED INDIVIDUALS MAY HAVE AN UNAFFECTED CHILD (25% CHANCE). Finding an unaffected child rules out a recessive trait. Recessive conditions are always homozygous and therefore all children will inherit the trait. 6) THE TRAIT WILL NOT (RE)APPEAR IN THE DESCENDENTS OF TWO UNAFFECTED INDIVIDUALS. Unlike recessives which could "skip a generation" 7) THE TRAIT MAY BE MORE SEVERE OR EVEN LETHAL IN THE HOMOZYGOUS STATE

autosomal dominance Caused by a defective gene for "fibrillin" a connective tissue protein important for the structure of bone and major blood vessels. This "disorder" is fairly rare affecting 1 in 10,000 individuals. Affected individuals tend to be excessively tall and have weak joints. The major hazard is that their Aorta may rupture when pressurized by the heart. Usually surgical repair and strengthening is possible if the condition is diagnosed early enough.

1) THE TRAIT IS EXPRESSED IN BOTH SEXES AND IS TRANSMITTED BY EITHER SEX TO BOTH MALE AND FEMALE OFSPRING IN ROUGHLY EQUAL NUMBERS. Indicates the trait is not sex inked and therefore is autosomal. 2) MOST AFFECTED INDIVIDUALS ARE THE CHILDREN OF UNAFFECTED PARENTS. Such erratic appearance is characteristic of recessive traits. 3) MATINGS BETWEEN AN AFFECTED AND AN UNAFFECTED INDIVIDUAL WILL USUALLY YEILD ALL UNAFFECTED OFSPRING. Since the trait "disappears" on mating with a "normal" (i.e. homozygous) individual, the trait must be recessive. 4) WHEN BOTH PARENTS ARE AFFECTED, ALL OF THEIR CHILDREN ARE AFFECTED. This finding is indicative of a homozygous state which is the expected situation for a recessive disease. 5) MATINGS BETWEEN UNAFFECTED HETEROZYGOTES YEILD ABOUT 3⁄4 UNAFFECTED AND 1⁄4 AFFECTED OFSPRING. This 3:1 ratio is expected for recessive traits. Occasionally such abrupt appearance indicates a common ancestor in the parent's families

Autosomal Recessive This condition is caused by a defect in a gene that controls salt and water transport from cells that line tube-like structures in the body. Cystic Fibrosis is relatively common in the Caucasian population 1 in 2000 births (~1 in 25 heterozygous carriers) but rare in Blacks and Asians. (salty kiss) As a result of the inability to control water flow into body ducts, thick, sticky secretions clog up these tubules, causing irreversible damage and malfunction in such organs as the lungs, pancreas, intestines, liver, sweat glands and (male) reproductive glands The main areas of concern are the -lack of pancreatic enzymes, which leads to malnutrition (cannot digest food and get nutrition) -clogging of the airways decreasing oxygen delivery. -supplemental digestive enzymes has minimized the nutritional problem and extended lifespan. Still pulmonary problems (obstruction, infection) limit lifespan and require continuous therapy. At present partial lung transplant is being used effectively in at least some cases. In addition there are plans to attempt a molecular genetic "cure" for this disease by inserting a "normal" gene back into the pulmonary tract of CF patients

Autosomal Recessive Caused by a defect in the gene for Hemoglobin, the oxygen carrying molecule of the blood. -West Africa, the Eastern Mediterranean and some sections of India as well as their descendants. -"resistance" to malaria (which is common in these regions) of individuals who are heterozygous for the Sickle Cell gene. -West Africa 1 in 50 show the disease while 1 in 500 of their American descendents are affected. -Sickle Cell Hemoglobin has only one wrong amino acid in its structure. However, this one change is sufficient to make the protein unstable when the O2 level is low. In this state Sickle-Hb aggregates into a rod and deforms the red blood cell (RBC) into a sickle shape. This deformed RBC can clog capillaries, which will; 1) cut of blood flow killing cells and causing organ malfunction and 2) increase blood pressure, stressing the heart and cause a heart attack. -high oxygen treatment -"blood thinning" drugs has prolonged the lifespan of affected individuals. -Modern plans hope to make use of an additional form of Hemoglobin that each person expresses during fetal life. If that form could be re-expressed during adult life the condition would essentially be cured

1) THERE IS NO MALE TO MALE TRANSMISSION OF THE TRAIT. This indicates the Y chromosome is not involved. 2) ALL DAUGHTERS OF AN AFFECTED MALE ARE AFFECTED. Indicates X-linkage - since autosomes are paired only 50% of daughters should get a particular allele. Also since the daughter receives one X from her mother the trait must be dominant. 3) AFFECTED FEMALES (probably heterozygous) MATED TO UNAFFECTED MALES PRODUCE OFFSPRING WHERE ONE HALF THE SONS AND DAUGHTERS ARE AFFECTED. Indicates X-linked dominant. 4) MALES ARE USUALLY MORE SEVERLY AFFECTED THAN FEMALES. While a heterozygous individual will have one "good" allele a "hemizygous" person does not. 5) EXPRESSION OF THE TRAIT IS MORE VARIABLE IN FEMALES. This is due to the random inactivation of one of the two X chromosomes. 6) IN THE GENERAL POPULATION THERE ARE TWICE AS MANY AFFECTED FEMALES THAN MALES. Females have two X chromosomes, males only one

*not enough phosphate in blood A rare disease (1 in 60,000) characterized by a low level of phosphate (and calcium) in the blood -defect in a kidney transport system which inhibits the reuptake (retention) of phosphate-->depresses intestinal absorption of calcium--> leads to softening and delayed growth of bone ex. bow legged, pain -begins in first year of life and into adulthood -no cure, but can be treated with daily oral phosphate, w/ vitamin D for bone growth -growth hormone supplements to promote bone growth and drugs to enhance kidney function

1) PHENOTYPIC EXPRESSION IS MUCH MORE COMMON IN MALES THAN IN FEMALES. This implicates some sort of sex-linked expression. 2) FATHER TO SON INHERITANCE IS NEVER SEEN. This rules out Y-linked and makes autosomal transmission unlikely. 3) AN UNAFFECTED MOTHER, MATING WITH AN UNAFFECTED MALE CAN PASS THE TRAIT TO 1⁄2 OF HER SONS. (THE TRAIT WILL NOT BE OBSERVED IN HER DAUGHTERS) This indicates X-linked transmission and that the trait is recessive (i.e. the heterozygous XX mother was unaffected). 4) "CARRIER" FEMALES OFTEN HAVE AFFECTED MALE RELATIVES AND/OR CARRIER FEMALE ANCESTORS. These heterozygous "carriers" may show some symptoms due to the random shutdown of one X chromosome (i.e. they are "mosaics)

red/green a defect in the color sensing mechanism of the eye. -8% of the male population in the U.S. For humans there are four types of light receptors in the retina of the eye; Rods for black and white and motion detection as well as Red, Green and Blue "Cones" for detailed and color vision. -light absorbing pigments of the retina are associated with a "holding" protein called an "opsin". There is a different opsin for each of the four detectors. *opsins is not produced or is defective. -effects only color perception not visual acuity. -can now benefit from color "enhancing" lenses

progressive muscle weakness and wasting (1 in 3500 males) *defect in dystrophin -muscles are injured or die because they lack the stretch of muscle -detected between 1-6 years of age, wheelchair by age of 12 -muscle deteriorates, organs connective tissue stiffens-->compression of chest can lead to heart failure -no cure, but therapy can lengthen life span -recent hopes on stem cell therapy

*is the inability of the blood to clot. 1) Hemophilia A has a frequency of 1 in 10,000 for males but only 1 in 100 million for females. Clot formation, or the ability of the blood to solidify, is important to prevent excessive loss of body fluids due to routine injury. -Clot formation in response to injury is a complex multi-step cascade (domino-like) process. Hemophilia (excessive blood loss) results when the protein involved in any one of the steps is missing or defective. The treatment for Hemophilia is periodic injections of the missing clotting factor. Originally this was painstakingly purified from donor blood but is now routinely produced by molecular genetic methods.

1) THE TRAIR PHENOTYPE IS SEEN ONLY IN MALES AND PASSED ONLY TO MALES 2) ALL OF THE SONS OF AN AFFECTED MALE SHOW THE TRAIT. Since males are "hemizygous" i.e. there is no comparable region on the X chromosome alleles on the Y will appear to act in a "dominant" fashion -only about 20 genes, involved in sexual development

INHERITANCE IS FROM MOTHERS TO ALL OFFSPRING. Males make no contribution -related to symbiotic bacteria -delivered from mother, sperm carries nuclear chromosomes to the egg

The range of phenotypes (e.g. disease severity) resulting from a given genotype

The probability that a disease phenotype (or trait) will appear when a disease-related genotype is present (i.e. the percent of individuals with the gene that express it)

a) Interaction of the disease gene with other genes in the genotype. b) Interaction between the genes and the environment

phenomenon, of "co-inheritance" of genes that physically reside on the same chromosome -do not easily separate during mitosis, are packaged into the same gamete

only show two categories of phenotypes - the parental combinations - not the four they actually showed

"arms" of homologous chromosomes (chromosome pairs) wrapped around one another and appeared to swap material

chromosome that exchanges alleles with its pair partner -independent assortment

shows relative position of genes along a chromosome, physical locations of specific genes on a chromosome