Human genetics describes the study of inheritance as it occurs in human beings.

Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling. Genes can be the common factor of the qualities of most human-inherited traits. Study of human genetics can be useful as it can answer questions about human nature, understand the diseases and development of effective disease treatment, and understand genetics of human life.

The

human genome is the genome of Homo sapiens, which is stored on 23

chromosome pairs. 22 of these are autosomal chromosome pairs, while the remaining pair is sex-determining. The haploid human genome occupies a total of just over 3 billion DNA base pair. Genetic information of human is encoded in two genomes: nuclear and mitochondrial. Both of them reflect molecular evolution of human starting from the beginning of life (about 4.5 billion years ago) until the origin of Homo sapiens species about 100000 years ago. From this reason human genome contains some features that are common for different groups of organisms and some features that are unique for Homo sapiens. 3.2 * 10^9 base pairs of human nuclear genome are packed into 23 chromosomes of different size. The smallest chromosome . 21st contains 5 *10^7 base pairs while the biggest one .1st contains 2.63*10^8 base pairs. Despite the fact that the nucleotide sequence of all chromosomes is established, the organisation of nuclear genome put still questions: for example: the exact number of genes encoded by the human genome is still unknown giving estimations from 30 to 150 thousand genes. Coding sequences represent a few percent of human nuclear genome. The majority of the genome is represented by repetitive sequences (about 50%) and non-coding unique sequences. This part of the genome is frequently wrongly called junk DNA. The distribution of genes on chromosomes is irregular, DNA fragments containing low percentage of GC pairs code lower number of genes than the fragments of high percentage of GC pairs.

HISTORICAL PERSPECTIVE- From the beginning of humanity, people have been interested in themselves. They were well aware of two aspects of living nature: an immense variability within each species and the tendency for characteristics of parents to be transmitted to their offspring. Already pre-Socratic philosophers noticed that people shared some characteristics, e.g .had usually, with some exceptions, two hands, a nose, large forehead, in other words they were alike. Probably the first person who publicly expressed his thoughts on the subject was Anaxagoras of Clazomenae. According to his teaching, seed materialis carried from all parts of the body to reproductive organs by the humors. Fertilization is the mixing of the seed material of father and mother. That all parts of the body participate in the production of seed material is documented by the fact that blue-eyed parents have blue-eyed children and bald headed men have sons that become bald headed. The idea of panspermy or pangenesis was adapted and taught by the famous physician Hipocrates (about 460377 B.C.) and was widely accepted until the end of the nineteenth century, also by Charles Darwin. One of the greatest scientists of all time, Aristotle of Stagira had a different view on the problem. Aristotles theory of inheritance, as described in one of his major works Degeneratione animalium, was holistic. He held that the contributions by males and females were not equal. The semen of the male contributes the form-giving principle, eidos, while the menstrual blood, cantemina , of the female is the unformed substance shaped by the eidos of the semen. The female always provides the material, the male provides that which fashions the material into shape; this in our view, is the specific characteristic of each sex: that is what it means to be male or to be female.(Aristotle, 1965).The twentieth century witnessed accelerated development of biology and with it the nature of the inheritance process was understood. Consequently, an effort to decipher the blueprint of our species has started. Several biological discoveries were especially important to decipher the human genome. Everything started with the rediscovery of Mendels laws by Hugo Marie De Vries (1900), followed by discovery of chromosomes by Thomas H.Morgan in 1910. In 1953 James D. Watson and Francis H.C. Crick unreveled the structure of DNA. Four years later, Johan H. Matthaei and Marshall Nirenberg performed experiments which enabled deciphering the genetic code. With the development of the fast methods of DNA sequencing in the mid-seventies,followed by automation of cloning and sequencing in the nineties, the way to understand our blueprint became clear. By now, many complete genomes of both prokaryotic and eukaryotic organisms have been sequenced. June26, 2000 marked a significant day in history when completion of a working draft of the human genome was announced worldwide, and reaserch in the field of human genetics entered a new dimension.

STRUCTURE OF HUMAN GENOME

GENERAL INFORMATION- Human genetic material is stored in two

organelles: nucleus and mitochondria. In nuclear genome 3.2 million bps are packed in 22 pairs of autosomes and two sex chromosomes, X and Y. Human chromosomes are not of equal sizes ; the smallest, chromosome 21, is 54 million bps long; the largest, chromosome 1, is almost five times bigger with 249 million bps. Genomic sequences can be divided in several ways. From the functional point of view we can distinguish genes, pseudogenes, and non-coding DNA. Only a minute fraction of the genome about 3% codes for proteins. There are many pseudogenes in the human genome (0.5%) but most of the genome consists of introns and intergenic DNA. Almost half of these sequences consist of different transposons; moreover, the remaining non-coding DNA most likely originated from transposable elements as well but with time they have mutated beyond recognition. This genetic sequence or genome is packed in highly condensed structures called the chromosomes. A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions. Chromosomes can be divided into two typesautosomes, and sex

chromosomes. Certain genetic traits are linked with the sex of an indivudial, and are passed on through the sex chromosomes. The autosomes contain the rest of the genetic hereditary information. All act in the same way during cell division. Human cells have 23 pairs of large linear nuclear chromosomes, giving a total of 46 per cell. In addition to these, human cells have many hundreds of copies of the mitochondrial genome. Sequencing of the human genome has provided a great deal of information about each of the chromosomes. Total chromosome length is an estimate as well, based on the estimated size of unsequenced heterochromatin regions.

Chromosome Genes 1 4,220 2 1,491 3 1,550 4 446 5 609 6 2,281 7 2,135 8 1,106 9 1,920 10 1,793 11 379 12 1,430 13 924 14 1,347 15 921 16 909 17 1,672 18 519 19 1,555 20 1,008 21 578 22 1,092 X (sex chromosome) 1,846 Y (sex chromosome) 454 Total 32,185

Total base 247,199,719 242,751,149 199,446,827 191,263,063 180,837,866 170,896,993 158,821,424 146,274,826 140,442,298 135,374,737 134,452,384 132,289,534 114,127,980 106,360,585 100,338,915 88,822,254 78,654,742 76,117,153 63,806,651 62,435,965 46,944,323 49,528,953 154,913,754 57,741,652 3,079,843,747

Sequenced bases[5] 224,999,719 237,712,649 194,704,827 187,297,063 177,702,766 167,273,993 154,952,424 142,612,826 120,312,298 131,624,737 131,130,853 130,303,534 95,559,980 88,290,585 81,341,915 78,884,754 77,800,220 74,656,155 55,785,651 59,505,254 34,171,998 34,893,953 151,058,754 25,121,652 2,857,698,560

Genes
There are estimated to be between 20,000 and 25,000 human protein-coding genes. The estimate of the number of human genes has been repeatedly revised down as genome sequence quality and gene finding methods have improved. Earlier predictions estimated that human cells had as many as 2,000,000 genes. Surprisingly, the number of human genes seems to be less than a factor of two greater than that of many much simpler organisms, such as the roundworm and the fruit fly. However, human cells make extensive use of alternative splicing to produce several different proteins from a single gene, and the human proteome is thought to be much larger than those of the aforementioned organisms. Besides, most human genes have multiple exons, and human introns are frequently much longer than the flanking exons.

Human genes are distributed unevenly across the chromosomes. Each chromosome contains various gene-rich and gene-poor regions, which seem to be correlated with chromosome bands and GC-content. The significance of these nonrandom patterns of gene density is not well understood. In addition to protein coding genes, the human genome contains thousands of RNA genes, including tRNA, ribosomal RNA, microRNA, and other non-coding RNA genes.

Regulatory sequences
The human genome has many different regulatory sequences which are crucial to controlling gene expression. These are typically short sequences that appear near or within genes. A systematic understanding of these regulatory sequences and how they together act as a gene regulatory network is only beginning to emerge from computational, high-throughput expression and comparative genomics studies. Some types of non-coding DNA are genetic "switches" that do not encode proteins, but do regulate when and where genes are expressed. Identification of regulatory sequences relies in part on evolutionary conservation. The evolutionary branch between the primates and mouse, for example, occurred 7090 million years ago. So computer comparisons of gene sequences that identify conserved non-coding sequences will be an indication of their importance in duties such as gene regulation. Another comparative genomic approach to locating regulatory sequences in humans is the gene sequencing of the puffer fish. These vertebrates have essentially the same genes and regulatory gene sequences as humans, but with only one-eighth the noncoding DNA. The compact DNA sequence of the puffer fish makes it much easier to locate the regulatory genes.

Other DNA
Protein-coding sequences (specifically, coding exons) comprise less than 1.5% of the human genome. Aside from genes and known regulatory sequences, the human genome contains vast regions of DNA the function of which, if any, remains unknown. These regions in fact comprise the vast majority, by some estimates 97%, of the human genome size. Much of this is composed of: Repeat elements Transposons Noncoding DNA

HUMAN GENETIC DISORDERS

A genetic disorder is an abnormal condition that is caused by an abnormality in an individual's DNA. These Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes. Among these chromosomal disorders are the most common. A chromosome anomaly, abnormality or aberration reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes. A Karyotype refers to a full set of chromosomes from an individual which can be compared to a "normal" Karyotype for the species via genetic testing. A chromosome anomaly may be detected or confirmed in this manner. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. There are many types of chromosome anomalies. They can be organized into two basic groups: numerical and structural anomalies.

Numerical Disorders
This is called Aneuploidy (an abnormal number of chromosomes), and occurs when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (Trisomy,Tetrasomy, etc). In humans an example of a condition caused by a numerical anomaly is Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of a monosomy where the individual is born with only one sex chromosome, an X.

Structural abnormalities
When the chromosome's structure is altered. This can take several forms: Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4. Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17. Translocations: When a portion of one chromosome is transferred to another chromosome. There are two main types of translocations: In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the Centromere in humans these only occur with chromosomes 13, 14, 15, 21 and 22. Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted.

 Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material. Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere. .

CHROMOSOMAL ANAMOLIES AND DIAGNOSIS OR GENETIC SCREENING

Chromosomal abnormalities can be diagnosed before birth using prenatal tests [amniocentesis or chorionic villus sampling (CVS)] or after birth using a blood test. Cells obtained from these tests are grown in the laboratory, and then their chromosomes are examined under a microscope. The lab makes a picture (karyotype) of all the persons chromosomes, arranged in order from largest to smallest. The karyotype shows the number, size and shape of the chromosomes and helps experts identify any abnormalities.

I.
II.

III.

Karyotype Analysis of Human Chromosomes Biochemical Estimations PEDIGREES

1. Karyotype preparation and analysis

Cells (from blood, amniotic fluid, etc) are grown in vitro (in a cell culture dish) to increase their number Cell division is then arrested in metaphase with colchicine (prevents mitotic spindle from forming) Cells are centrifuged and lysed to release chromosomes Chromosomes are stained, photographed, and grouped by size and banding patterns This is a photograph of the 46 human chromosomes in a somatic cell, arrested in metphase. 2. Normal male karyotype

3. Normal female karyotype

Down Syndrome: Down syndrome (DS) is a genetic disorder that is caused by an extra chromosome 21 that is present in all or some of the individual's cells. There are three types of chromosome abnormalities in Down syndrome. The first

is called trisomy 21 and is the most common form of DS. With trisomy 21, the individual has an extra chromosome 21, which results in a total of 47 chromosomes in each cell rather than the typical 46. DS is one of the most common chromosome abnormalities. It is estimated that the incidence is between 1 in 800 to 1,000 live births. There are many physical characteristics that are associated with DS. Not every individual has all the characteristics, however, the following is a list of the most common traits: Low muscle tone Flat facial profile (depressed nasal bridge and small nose) Flattening of the back of the head Small hands and feet An upward slant of the eyes An abnormal shape of the ear A single deep crease across the center of the palm An excessive ability to extend the joints Fifth finger has one flexion furrow instead of two Small skin folds on the inner corner of the eyes Excessive space between large and second toe Enlargement of tongue in relation to the size of the mouth Mental retardation (can range from very mild to severe, however, is typically mild to moderate) Speech delays Short stature KARYOTYPE WITH DOWNS SYNDROME:

Patau syndrome (trisomy 13): Serious eye, brain, circulatory defects as well as cleft palate. 1:5000 live births. Children rarely live more than a few months.

Edward's syndrome (trisomy 18): Almost every organ system affected. 1:10,000 live births. Children with full Trisomy 18 generally do not live more than a few months.

Klinefelter syndrome: 47, XXY Klinefelter syndrome, also known as the XXY condition, is a term used to describe males who have an extra X chromosome

in most of their cells. Instead of having the usual XY chromosome pattern that most males have, these men have an XXY pattern.

.Male sex organs; unusually small testes, sterile. feminine body characteristics. Normal intelligence. Abnormal body proportions (long legs, short trunk, shoulder equal to hip size) Abnormally large breasts (gynecomastia) Infertility Sexual problems Less than normal amount of pubic, armpit, and facial hair Small, firm testicles.

The following tests may be performed :

Karyotyping Semen count

KARYOTYPE WITH KLINEFELTER SYNDROME:

Treatment
Testosterone therapy may be prescribed

Monosomy X (Turner's syndrome): 1:5000 live births; the only viable monosomy in humans. Women with Turner's syndrome have only 45

chromosomes. XO individuals are genetically female, however, they do not mature sexually during puberty and are sterile. Short stature and normal intelligence. (98% of these fetuses die before birth)

47, XYY males: Individuals are somewhat taller than average and often have below normal intelligence. At one time (~1970s), it was thought that these men were likely to be criminally aggressive, but this hypothesis has been disproven over time.

3. Trisomy X: 47, XXX females. XXX syndrome (also called Trisomy X or Triple X) is caused by the presence of an extra X chromosome in every cell. Typically, a female has two X chromosomes in every cell of their body, so the extra X is unusual 1:1000 live births , healthy and fertile - usually cannot be distinguished from normal female. Many girls and women with Triple X have no signs or symptoms. Signs and symptoms vary a lot between individuals, but can include:

Physical: o Tall stature (height) o Possible mild facial characteristics: increased width between eyes, skin fold at inner eyelid (epicanthal fold), proportionately smaller head size Developmental: o Learning disabilities (70%): Normal IQ, but may be 10-15 points below siblings o Speech and language delays (50%) o Delayed motor skills: poor coordination, awkwardness, clumsiness Behavioral: introverted, difficulty with interpersonal relationships

Cri du chat (cry of the cat): A specific deletion of a small portion of chromosome 5, these children have severe mental retardation, a small head with unusual facial features, and a cry that sounds like a distressed cat.

Fragile X: The most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip - seen "hanging by a thread" under a microscope. Most people have 29 "repeats" at this end of their Xchromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females. .

ACUTE MYELOGENOUS LYMPHOMA- Translocation: a fragment of a chromosome is moved ("trans-located") from one chromosome to another - joins a non-homologous chromosome. The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment. Can also cause difficulties in egg or sperm development and normal development of a zygote. Acute Myelogenous Leukemia is caused by thistranslocation:

I I PEDIGREE
A pedigree is a diagram showing the ancestral relationships and transmission of genetic traits over several generations in a family. Pedigrees are used to help detect many different genetic diseases. A pedigree can also be used to help determine the chances for a parent to produce an offspring with a specific trait. Four different traits can be identified by pedigree chart analysis: Autosomal dominant, Autosomal recessive, X-linked, or Y-linked. Pedigrees are a convention for keeping track of human genetic traits used to infer genotype. Pedigrees are the human equivalent of test crosses.

In a visualization of a pedigree:
i. ii. iii. iv. Males are designated with square symbols. Females with round symbols Lines are drawn to indicated matings, parent-offspring relationships, and relationships between siblings. Traits associated with dominant, recessive, sex linked, etc. alleles and loci display characteristic patterns in pedigrees just as they do when following traits in any organism by any means (i.e., in addition to historical). The origin of these patterns are discussed below.

The utility and use of PEDIGREE can be very well understood by taking the very famous example of Hemophilia: The Royal Disease . Hemophilia is an X-linked recessive disorder characterized by the inability to properly form blood clots. Until recently, hemophilia was untreatable, and only a few hemophiliacs survived to reproductive age because any small cut or internal hemorrhaging after even a minor bruise were fatal. Now hemophilia is treated with blood transfusions and infusions of a blood derived substance known as anti-hemophilic factor. However, such treatment is very expensive and involves the risk of contracting AIDS. Hemophilia affects males much more frequently (1 in 10,000) than females (1 in 100,000,000). This occurs because a critical blood clotting gene is carried on the X chromosome. Since males only carry one X chromosome, if that is defective, hemophilia will immediately show up. An early death is likely. Females, on the other hand, carry two X chromosomes. If only one is defective, the other normal X chromosome can compensate. The woman will have normal blood clotting; she will simply be a carri er of the recessive defective gene. This fact will be discovered if some of her children are hemophiliacs. Naturally, women hemophiliacs are rare because it takes two defective X chromosomes in order for the condition to be seen. Hemophilia has played an important role in Europes history, for it suddenly cropped up in the children of Great Britains Queen Victoria. It became known as the Royal disease because it spread to the royal families of Europe through Victorias descendants. Queen Victoria had always been worried about the quality of the blood of the British royal family. The appearance of hemophilia in one of Victorias sons upset and confused the Queen, who could only protest that the disease did not originate in her side of the family. Yet, a whisper about the curse of the Coburgs was spread about. This curse was supposed to have dated from the early nineteenth century, when a Coburg prince had married a Hungarian princess named Antoinette de Kohary. A monk, a member of the Kohary family, envied the wealth inherited by the happy couple from the brides father, and cursed future generations of Coburgs with the disease. Of course, hemophilia affecting Victorias offspring had nothing to do with the curse. The traditional view is that there was a mutation in either her or in a sperm of her father, Edward Augustus, Duke of Kent. From there it spread through the Royal Houses of Europe as monarchs arranged marriages to consolidate political alliances. We can trace the appearance of hemophilia

as it popped up in Spain, Russia, and Prussia by looking at the family tree.