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Sunday, September 22, 2019
Twins Genetics Essay Example for Free
Twins Genetics Essay Introduction Twin pregnancies still face greatest challenges in obstetric care and fetal medicine today. Much is known about the diseases by studying the development of infants who have shared the same foetuses. Pregnancies occurring with twins have a higher incidence of preterm labour, miscarriage and fetal death when compared to single pregnancies. Non-identical twins (dizygous, binovular, fraternal, or dizygotic) result from the fertilization of two independently released ova by two different sperm. Their genetic makeup is as dissimilar as one would expect between siblings. All these twins possess separate amnion sac. Whereas, identical twins (monozygous, uniovular, monozygotic) arise from the splitting of a single fertilized egg within the first 14 days after fertilization. Monozygous twins, depending on the timing of embryonic cleavage, may be dichorionic diamniotic (d1–3), monochorionic diamniotic (MCDA) (d3–8), monochorionic monoamniotic (d9–12), or conjoined, when cleavage of the embryo occurs on day 12 or beyond (Farah Siddiqui, 2007). Monozygotic twins although, considered genetically identical, but there may exist a significant phenotypic discordance especially in the psychiatric diseases like schizophrenia and bipolar disorder.  (Mario F. Fraga, 2004)            The history behind using Twins to investigate the role of heredity and environment in human life heads back to 19th century. Francis Galton. Charles Darwin cousin was the first researcher to think of this. Since, then twins are been considered as aspects of study in biology, medicine and psychology. Galton thought that since twin pairs (both identical and non-identical) share the same environment, there will be greater coordination of the genetic factors in the disease in genetically identical twins compared to non identical twins. But, by contrast, similar coordination rates for a disease in twins pairs (both identical and non-identical), or differences between the identical twins, suggest that the disease is probably due to non-genetical factors. Twin studies have been many times used to estimate the impact of genetic factors on the disease cause. It is believed that a genetic effect is suggested when the concordinance rate is identical twins exceeds that in nonidentical twins. The concordinance rate in the both identical and nonidentical twins in population based studies suggested that in case of multiple sclerosis there is 27% occurrence compared of the latter which is 3%. Similarly, Rheumatoid arthritis occurrence in former in 12.3% compared to the latter which is 3.5%. Whereas in systemic lupus erythematosus the concordance rate in nonidentical twin was nil compared to the identical twin, where the rate were 33% (Marco Salvetti, 2000). Twin studies also have the possiblity of assesing other applications in the assessment of aspects of potential relevance in the pathogenesis of autoimmune diseases. There are possible precipitating factors of autoimmune conditions that await definition including epigenetic effects due to DNA aor protein modifications, the accumulation of somatic mitochondrial DNA mutations, X chromosme incativation and the transcriptionally active endogeneous retroviral sequences presence (Marco Salvetti, 2000).            This contribution discusses the difference in the monozygous twins in which factors like the timings of monozygous twinning, linguistic differences and the genetic mechanism are discussed. There are many differences observed among twin pairs like mirror twinning, hair eye, and finger prints etc. without any known reasons or in other word we have very limited understanding of why these kind of differences arises?. In case of mirror twinning almost 25% of twins have differences and most common is handedness where both twin used different hand for particular purpose. The difference due to any unknown mechanism is also included.               The biggest challenge faced by investigators for evaluating genetic basis of complex disease is to identify small number of genes responsible for disease among thousands of genes present in whole genome in addition to that environmental effect makes task more difficult. Thus development of ideal model system to investigate genetic basis of disease becomes primary requirements. In the following some of the case studies where twins were used as model system for explain genetic bases of diseases are discussed including factors like immunity, leukemia, infectious and autoimmune diseases.  A `corpus`  Mechanisms for differences in monozygous twins:                                 In general perception Monozygous (MZ) twins are physically and genetically identical. Similarly, clinical determination of zygosity relies on the assumption that any physical differences between a pair of twins imply they are dizygous. As per the other perception dizygous twins share approximately 50% of the same genes, whereas monozygous twins share 100%. But advancement in molecular techniques and understanding of genetics of twins puts several question marks on above mention perception as there are many exception regarding genetic composition and physical appearance of mono and dizygotic twins. There are many numbers of intrauterine effects and other mechanisms that may result in phenotypic, genotypic, and epigenetic differences between monozygous twins. Some of those mechanisms are as follows. Timing of monozygous twinning:                Monozygous (MZ) twinning occurs when single fertilized egg give rise to two separate embryos and timing of this separation decides the post zygotic differences in upcoming twins. As early the separation there will be less similarity and late the separation there will be more similarity. During development if the two embryos are separated at latter part most of the differentiation processes completed before they separate and hence both offspring have similar origin. The extreme example of late twining is twins having common somatic organ (Conjoined twins). While in case of early separation the process of differentiation occurs independently which leads to creation of differences among of springs. If twining occurs 8 days after the fertilization and before 12th day the twins are quite identical to each other and called as monozygotic twins comprises of almost 5% of total twins. Genetic mechanisms:                        It is widely believed that monozygotic twins are genetically identical and any differences among them are result of environmental influence. But there is an ever-growing body of evidence that monozygotic twins are not always genetically identical. A number of phenotypic variations in monozygotic twins have been demonstrated to be caused by genetic differences alone and not influence by ante-natal environmental factors. In addition epigenetic modifications in particular sets of gene within a monozygotic twin pair leads to altered expression and hence contribute towards differences. (Paul Gringrasa, 2001). Genetically monozygotic twins can be different at the level of chromosome (number or morphology of chromosome) or DNA (mutation, epigenetic modification). At chromosome level variation classical example is gender difference and certain diseases like Turner syndrome (XYY) this is mainly happened due to early post zygotic mitotic error, resulting in heterokaryotic twining that involves nondisjunction or anaphase lag of the Y chromosome. While at DNA level there are mainly three mechanisms by which differences arises for example differential methylation of CpG island leads to inactivation or activation of particular gene and which contribute in causing differences among monozygotic twins. Not only that, this process of methylation is key factor for inactivation of whole X chromosome and many X-linked diseases like fragile-X, colour blindness, are result of this inactivation. Similarly post zygotic mutation leads to emergence of differences among monozygotic twins. Differences due to some unknown mechanism:               There are many differences observed among twin pairs like mirror twinning, hair eye, and finger prints etc. without any known reasons or in other words we have very limited understanding of why these kinds of differences arises? In case of mirror twinning almost 25% of twins have differences and most common is handedness where both twin used different hand for particular purpose. The reason behind this was thought to be due to asymmetry of cerebral hemisphere dominance. Similarly, hair and eye colour were know to be the identification mark for dizygotic twins but now it was realized the there are many instances where the differences were observed in MZ too. The reason behind these differences are not well understood and thought to be due to complex genetic interaction and post zygotic mutation. Linguistic differences:                Twin based heritability estimates for language rarely exceeds 0.6 and for monozygotic twins in many instances they were found to be very different. In addition to that it was found that MZ are more likely to suffer linguistic delay and impairment than singletons. There are many factors which affect or create these differences like genetic, epigenetic and prenatal environmental factors. Meta-analyzed data from almost 100 twin studies indicate that depending on what aspect of language is assessed, heritable factors account for between 1/2 to 2/3’s of the variance in language- impaired twins’ linguistic abilities and 1/4 to 1/2 of the variance in normal twins’ linguistic abilities. These meta-analyses also reveal that for both languages impaired and normal twins (Stromswold, 2006). The major contributory factors among perinatal environmental conditions are low birth weight, premature birth, Placental and amniotic complications, Intrauterine infections, neonatal hyperbilirubinea, brain injuries to language area etc. similarly post natal factors includes language input, parental role etc. There are no well documented genetic factors influencing the language in isolation and always studied in light of environmental influence. Twins and genetics and diseases:                    The biggest challenge faced by investigators for evaluating genetic basis of complex disease is to identify small number of genes responsible for disease among thousands of genes present in whole genome in addition to that environmental effect makes task more difficult. Thus development of ideal model system to investigate genetic basis of disease becomes primary requirements. The study of twins become central stage for this kind of investigation for example in case of non-identical twins there are some  similarity like age, family environment and background environmental variation while they have different genetic makeup, Provides excellent tool to determined effect of genetic makeup on diseases. While in case of identical twins, similarity in genetic makeup provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact. Followings are some of the case studies where twins were used as model system for explain genetic bases of diseases. (Alex J. MacGregor, 2000) Twins and immunity:                  Immunological disorders are some of the widely observed phenomenon and almost 5% of total population is suffering from these disorders, including insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS) and coeliac disease. Strong correlation between genetic makeup and immunological disorder were established based on various twins’ studies. Here in this particular case the complexity of disease and involvement of genetic as well as environmental factors makes twin studies a right system for investigation where investigators can fix one parameter (genetic makeup in case of identical twins) and other variable to evaluate effect of other factor (i.e. environment). Initially genetic and environmental factors are both thought to contribute to the pathogenesis of immune-mediated diseases. But after employment of twins based study strongly rejected the above argument and clearly demonstrated that environment is the major contributor towards immune disease. Twins study demonstrated that the majority of identical twins with an autoimmune disease have an unaffected twin (Table 1). Table 1. Concordance rates in identical and non-identical twin pairs in population-based                    Studies of immune-mediated diseases Disease Identical twin pairs (%) Non Identical twin pairs MS 26.7 3.5 RA 12.3 3.5 IDDM 13 2.5 SLE 33 0 (Marco Salvetti, 2000) In some cases initially unaffected twin may develop the clinical disease some years after the index twin, but that was not statistically significant. As the majority remain unaffected on prospective study. But one should remember that even identical twins can differ genetically for example X-chromosome inactivation in females. And differential methylation of CpG Island leads to expression of entirely different sets of genes. Similarly there are several somatic rearrangement occurred during T cell receptor development and antibody production and thus differential disease susceptibility in identical twins may be due to effect of non genetic (epigenetic) factor on genetic. Similarly, one should note the fact that observed frequency of particular disease (table1) found to be more in case of identical twins compared to non identical twins clearly indicates role of genetic factor. In conclusion for immune diseases environmental factors play major role in light of genetic background. Twins and Leukemia:                      The first report of concordant leukemia in twin children appeared in the German literature in 1882 and then after many reports came in similar lines, Most of these studies indicated that there is almost 5-15% concordance rate among monozygotic twins and there are significant differences observed in case of different type of leukemia and age. But surprisingly in case of adult twins the concordant was found to be less than 1% which clearly indicated prenatal origin of disease. The risk estimation of likelihoods of occurrence of disease in co twin is not quite accurate but they can be consider as reasonable guide and approaching 100% for infant while risk of the order of 1 in 10 for older children. This estimation is valid for monozygotic twins and those who have monochrorionic placenta. (Mel F. Greaves, 2003) Twins and infectious diseases:            There are several observations that clearly indicate infectious diseases have an inherited element, and individuals respond differently to particular infections. The behavior of infectious agents can vary so greatly between strains that the effects of individual Variation are best seen when the same strain of an organism simultaneously infects previously unexposed individuals. Twin studies have compared the disease status among identical and non-identical twins, with the expectation that disease concordance will be higher in identical twins for a disease with a genetically determined component. (Table 3). Even though there are numerous studies carried out to identify major gene responsible for diseases susceptibility there was no clear picture appears for the same.  The major contribution for diffrential suceptibility of infectious disease came for variation in HLA (major histocompatibility complex), T cell recptor and diffrential V-D-J recombination among twins. The environmental factor here  played very crucial role. Table: 3 Table depicting the concordance of disease percentage in both Monozygotic and Dizygotic twins, accordance to the country. (Hill, 2001)  Disease Concordance* Country MZ (%) DZ (%) Tuberculosis  Germany USA UK 65 62 32 25 18 14 Leprosy India 52 22 Poliomyelitis USA 36  6 Hepatitis B Taiwan 35 4 Possibility of twins having twins:    Birth of Identical or monozygotic twins dose not run in to the family but non identical of dizygotic twins have some heridetory influence. The main reason behind this is monozygotic twins are developed from single fertilized egg while non identical twins develop from two egges shed by ovary. The process of egg shedding have genetic manifestation and observed in woman having family history of twins.In conclusion, a mother of fraternal twins is 3-4 times more likely to have another set of fraternal twins. A woman who is an identical twin is no more likely to have twins compared to someone else expecting. Conclusion:               Twins were consider to be an ideal model system to understand influence of genetic and environmental factors on various aspect of human life including diseases susceptibility, metabolism, social behavior, IQ, personality, linguistic proficiency, Behavior etc. But the biggest challenges were to understand influence of individual factors on overall development of twins. In ideal condition MZ twins considered to be genetically and physiologically identical but there are many exceptions and that is mainly Due to post zygotic mutation and epigenetic influence along with well studied environmental factors. Similarly Immunity and disease susceptibility is mainly influence by environment and partly by genetic factor. For certain diseases like cancer, preventive measures should be taken in case of one of the twin diagnosed with disease, as chances of emergence of same disease in co-twin are high.                    If the potential of twin studies is to be realized there should be strong collaboration between clinician, scientist and data management agency. Till recent past the main emphasis were given to genetic and environmental factors for any differences among twins. But development of newer technology based on molecular biology changes our perceptions. The epigenetic factors emerge as key contributor towards onset of physiological changes among twins at old age. Careful investigation along with new technology makes twin studies more useful with conclusive answer of various problems. Bibliography Alex J. MacGregor, H. S. (2000). novel uses to study complex traits and genetic diseases. TRENDS IN GENETICS , 131-134. Farah Siddiqui, A. M. (2007). Twins. OBDTETRICS, GYNAECOLGY AND REPRODUCTIVE MEDICINE, 289-295. Hill, G. S. (2001). GENETICS OF SUSCEPTIBILITY TO HUMAN INFECTIOUS DISEASE. NATURE REVIEWS GENETICS , 967-977. Marco Salvetti, G. R. (2000). Twins: mirrors of the immune system. IMMUNOLOGY TODAY . Mario F. Fraga*, E. B. (2004). Epigenetic differences arise during the lifetime. PROCEEDING OF NATIONAL ACADEMY OF SCIENCES , 10604-10609. Mel F. Greaves, A. T. (2003). Leukemia in twins: lessons in natural history. BLOOD , 2321-2331. Paul Gringrasa, ,. W. (2001). Mechanisms for differences in monozygous twins. EARLY HUMAN DEVELOPMENT, 105-117. Stromswold, K. (2006). Why aren’t identical twins linguistically identical? Genetic, prenatal and postnatal factors. COGNITION , 333-386.
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