Genes and genetic disorders

If we think about how amazing it has been  the Human Genome project, how much we have learned from it and everything that has been generated so far, it's impossible to ignore the value of genomics, for example,  initially was thought that our 46 chromosomes were composed of 100,000 protein-coding genes, enzymes, hormones and overall regulatory sources of all life processes that shape human characteristics but now is possible to begin to manipulate all of them  to heal syndromes and diseases.

Chromosome 22 was the first to be fully identified 545 genes having assets, followed later by genetic mapping or sequencing of chromosome 21, with only 225 active genes, which opened the possibilities for genetic treatments medical situations as Down Syndrome, a form of Alzheimer's disease and various cancers.

Thus began the race to find a specific gene for each of the major conditions that afflict humans. At the same time, it have been found the relationship between the production of proteins and some genes that create on protein production and others that inhibit the production of the same.

In this sense it was found some genes associated with autism spectrum syndromes such as 15q11-q13, 2q37.3 or UBE3A for Angelman syndrome, which has also been associated with the GABRB3 gene, whereas for the syndrome Williams is the gene 7q11.23; MeCP2 for Rett syndrome, to mention only the best known developmental syndromes.

However, it is known that there are more syndromes, such as West syndrome that is associated with the ARX gene, or even lower prevalence may be mentioned De Lange syndrome or Crohn's disease, whose genetic alteration is in 5p13.1 gene.

Talking about less common syndromes we can talk about Smith-Magenis syndrome which is associated with  17p11.2 gene, or the VCFS 22q11 gene related, with myotonic dystrophy which is a multisystem disease whose genetic alteration is associated with the repetition CTG trinucleotide on chromosome 19.

While the tuberous sclerosis complex (TSC), which is an autosomal dominant inherited disease which may be due to the mutation of two distinct genes: TSC1 (9q34) and TSC2 (16p13.3).

Timothy syndrome caused by a mutation in the gene CACNA1C located in 12p13.3, other forms of alteration as 10p terminal deletion, has been associated with a phenotype similar to DiGeorg syndrome causing hiccups hyperparathyroidism, deafness sensory abnormalities stones.

Moreover, it has been  studied the gene involved with 45X/46XY mosaicism, or we can mention Cowden syndrome is associated with PTEN gene, which is located at 10q23.3.

Another group of genetic disorders like Goldenhar syndrome are related  to deletion 5q (Artigas-Pallares, Gabau-Vila & Guitart-Feliubadaló, 2005), all associated with developmental disorders.

Whereas if you look at the studies on cancer have been found, for example for brain cancer, NFkB protein with much higher activity than in normal brains or HER2 protein in lung and breast cancer, BCR- AB1 for chronic myelogenous leukemia, RAS, for several types of cancer, B-RAF for skin cancer, BCL-3 for lymphoma; RB1 for retinoblastoma, HNPCC for colon cancer and endometrial, the p53 gene causes cell suicide and is associated with cancer of the lung, colon, breast and brain (Collins and Barker, 2008).

It's not possible to forget disorders of cognitive processes such as Alzheimer's,  so it's possible to find genetic associations with cognitive processes, although further studies are not conclusive, for instance mentioned the IGF2R gene associated with intelligence, which is a very popular topic.

That is why around 1980 Dr. Plomin, from Institute of Psychiatry, at London, England, began his research on genes and intelligence relationship, since observed that two people with the same genes correlate as much as the same person performing an intelligence test with a year of difference, so he realized that identical twins who live apart are very similar or identical in intelligence tests that identical twins who live together, which is why it is considered that the environment influences the development of children, however it has become clear that genes can shape the brain in ways that make individuals better or worse to answer an intelligence test.

Despite this, Plomin suspect that more markers are needed to find the genes for intelligence, but states that exist many difficult to replicate details to affirm conclusively that have these genes (Silverman, 2008).


More consistently it was found the  called language gene, which from the genetic standpoint is associated with the specific disorder of the cognitive process, which seems to be due to alteration of a small number of key genes and in particular FOXP2 gene mutation.


The gene in question is expressed primarily in certain areas of the central nervous system, both during embryonic development and in the adult individual, but is also expressed in other regions during embryo development, such as lung, intestine and heart, and in different tissues of the adult. However, affected individuals with language impairment, have a non-mutated copy of the gene (Burraco Benitez, 2005; 2006; Gopnik and Crago, 1991).


Although each day is more advanced in the study of genes and the proteome, considering that it is estimated that there are about 4000 genetic disorders, and so far has been identified only a little more than 60 genes involved in diseases, no doubt the work will take several years before conclusion, but in spite of all the implications of research some point that knowledge of the human genome will be the main focus in the diagnosis and treatment for a large number of diseases such as diabetes, cardiovascular disease, mental and many forms of cancer.

References: 

Artigas-Pallarés, J., E. Gabau-Vila, E., Guitart-Feliubadaló, M.  (2005) El autismo sindrómico: II. Síndromes de base genética asociados a autismo. Rev Neurol. 40 (Supl 1): S151-S162.

Benítez – Burraco, A. (2006) Genes y lenguaje. Teorema Vol. XXVI/1, 37-71.

           

Benitez-Burraco, A. (2005) FOXP2: del trastorno específico a la biología molecular del lenguaje. I. Aspectos etiológicos, neuroanatómicos, neurofisiológicos y moleculares. Rev Neurol.  40 (11): 671-682.

Collins, F. and Barker, A. (2008) Mapping the cancer genome. Scientific American Special Edition: New answers for cancer. Vol. 18. Num. 3. 22-29.

Gopnik, M. y M. B. Crago (1991) Familial aggregation of a developmental language disorder.  Cognition. 39. 1-19.

Hayden, KE., Strome, ED., Merret, SL., Lee, HR., Rudd MK., Willard, HF. (2013) Sequences Associated with centromere competence in human genome. Molecular and Cellular Biology. 33 (4) 763-772.

Weischenfeld, J., Symmons, O., Spitz, F.,&  Korbel, J. (2013) Phenotypic impact of genomic structural variation: insights from and for human disease. Nature Reviews Genetics. 14. 125-138.

 Young, E. (2013) Shutting down the extra chromosome in Down's Syndrom cells. National Geographic: Phenomena: Not exactly rocket science. Disponible en: http://phenomena.nationalgeographic.com/2013/07/17/how-to-shut-down-the-extra-chromosome-in-downs-syndrome/

The human genome

Following our little story about DNA, after the first research that explained the composition of this called molecule of life, researchers continued trying to understand the genetic makeup of human beings.

Something clear after the first findings about normal human genome, it's the fact this consists of 23 pairs of chromosomes, those inherited by mother andthose inherited by  father, but in total there are 24 pairs of chromosomes since  2 correspond to the sexual chromosomes X and the and, Y which harnessed on XX if you are female and XY if you are a male.
 

This is part of the working material of the genetic, which is responsible of researching  heritage and vulnerability of specific the genotypic traits and the genes associated with them. On the other hand, the new science called  Genomics sees genome as a whole, even their multiple interactions with environmental factors, resulting in perceptible all the individual organism. For this purpose it has methodological tools that allow you to study at a time, globally or in parallel, a single biological sample, thousands of genes or their products (Velázquez, 2004).

These gene sequences control most bodily functions and structures, such as the creation of organs, connection between  neurons in the nervous system, skin color, color of eyes, etc.,  however, in order to those genes exert their specific action is required in addition to their structural and functional integrity the presence of a suitable environment. 

Other two fundamental genetic concepts are genotype and phenotype, the first refers to an individual's genetic constitution is  genome specific to an individual, in the form of DNA, while phenotype refers to what is related with  apparent characteristics as  factions,  color of eyes,  timbre of the voice. Then we can say,  genotype can be defined as the set of genes of an organism and the phenotype as a set of traits of an organism.

So the generation of  diversity of races and physical features is  made by a genetic recombination which undergoes each generation, but each individual is genetically different from everyone else (except if you have an identical twin), since the variety of ovules  or sperm that are formed along the life is so great, for practical purposes  only can say that none of them is equal to the other. Thus, mutations are the specific material of genetic diversity, but is is even greater and less controllable in species with sexual reproduction, which constantly faces  different genomes.

Genome (is a word made up of genes and chromosome) and is the totality of genetic material of an individual that contains the information for the operation and the development of a new body, since the ovule  is fertilized by the sperm until the end of life (Kaessmann & Pääbo, 2002; Velázquez, 2004).

With all that  information emerges with its own light the Human genome project (HGP), which constitutes the greatest scientific adventure of human biology and the genetic map  known. Through this project now we know an important basis of the medicine of the future. 

The Human Genome Project is an international research  whose ultimate goal is a complete description of the human genome, through DNA sequencing. It is known that the human genome consists of 3 billion base pairs, which can be comparable to an encyclopedia composed of thousand volumes, each with a thousand pages and 3,000 letters per page. If the bases would be the letters; the genes are the words and phrases,  while the chromosomes would be different volumes of the encyclopedia. Once completed the sequencing of the human mitochondrial genome, the next step was   investigating the nuclear genome. Given the scale of the effort that goes into the project, it represents what this is the first project of great science in biology (Velázquez, 2004).

But all this sequence is not easy, since the term human genome is used to describe all of the genetic information (DNA content) of human cells. In fact, encompasses two genomes: a complex, nuclear genome, and a simple, mitochondrial genome.

Research shows that nuclear genome  contains more than 99% of cellular DNA, has a total of 3000 Megabases (Mb) which are distributed among 46 chromosomes, 22 different autosomal pairs and two sex chromosomes, which can be distinguished through the application of chromosome banding techniques.

The number of genes containing the nuclear genome is estimated in a range that ranges between 30,000 and 150,000. While the human mitochondrial genome is defined by a single type of DNA. Its nucleotide sequence has already been fully established and consists of 16,569 base pairs in length that contain 37 genes. Unlike its nuclear counterpart, the human mitochondrial genome is extremely compact, approximately 93% of their DNA sequence is coding.

 In the nuclear genome, the percentage of coding DNA is only 3%, the remaining 97%, whose importance is a cause for controversy, it has been improperly called Junk  DNA. But, he found, however, that plays a key role in the normal function of the genome, the repair and regulation, and perhaps even in the evolution of multicellular organisms. On the other hand, public and private human genome project drafts have revealed that all human are identical in 99.8% (Glusman, Sosinky, Ben-Asher, Avidan, Sonkin and Bahar, 2001). 

But the effort to decode the human genome, has been an adventure that has been possible at different stages. The first began in the 1950s, when James Watson and Francis Crick in 1953 discovered the helical structure of DNA.

 Later multiple researchers are added with discoveries key as the Paul Berg and collaborators, who in 1972 created the first recombinant DNA molecule, and scientists from Harvard University and the United Kingdom developed a technique for sequencing DNA.

 In the Decade of the 80s in a joint effort between the universities of Stanford, Utah, Japan and other countries proposes a method for mapping the entire human genome. A genetic map consists of several genetic markers located nearby, one of whose order has been able to determine along each of the chromosomes, as a physical map, which becomes an enormous collection of small chromosome fragments also sorted according to its relative position in their corresponding chromosomes. 

After that, efforts focused on which markers and in which order they are in each one of the fragments of the physical map, similar as pieces of a puzzle, if two fragments share one or more genetic markers, this indicates that the two fragments are contiguous. Thus the genetic map to know the order that saved between if the fragments of the physical map (Velázquez, 2004).

With the development in 1985 of PCR (polymerase chain reaction) by Kary Mullis and his  partners to replicate DNA,  different studies were performed to sequence models of micro-organisms. But it was until 1995 that was published genetic mapping of the first living organism: Haemophilus influenzae which consisting of 1740 genes. This technique aims to obtain a large number of copies of a particular DNA fragment, on the basis of a minimum; in theory just starting from a single copy of this original fragment,  it's possible to amplify a fragment of DNA.  Its utility is so huge because  after amplification, it is much easier to identify with a very high probability of disease-causing by bacteria or viruses, identify people (bodies), or do scientific research on the amplified DNA (Bartlett & Stirling, 2003).

References: 

Bartlett, D. & Stirling, H.  (2003) A Short History of the Polymerase Chain Reaction. Methods Mol Biol. 226:3-6.

Glusman, G. Sosinky, E., Ben-Asher, N. Avidan, D. Sonkin, A Bahar, D. (2001) Sequence, structure and evolution of a complete human olfatory receptor gene cluster. Genomics. 63: 227-245.

Kaessmann, H. & Pääbo, S. (2002) The genetical history of humans and the great apes. Journal of Internal Medicine. 251. 1-18.

National Human Genome Research Institute (SF) A brief history of the Human Genome Project. Available at: http://www.genome.gov/12011239

Velázquez, A. (2004) Lo que somos y el genoma humano: des-velando nuestra identidad. Ediciones científicas universitarias. UNAM. FCE.

Strathern, P. (1999) Crick, Watson y el ADN. Siglo Veintiuno Editores. España.

Watson, J. (2000) La doble hélice. Alianza Editorial. Madrid.