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UNDERSTANDING THE COMPLEXITY OF GENES AND DISEASES IN INDONESIAN ARCHIPELAGO Herawati Sudoyo Eijkman Institute for Molecular Biology Jakarta, Indonesia Health systems complexity: Bridging Physiome with Health Care through Computational Modelling Symposium, NITH-NTU, Singapore, 26 January 2015 GENNEKA TUNGGAL IKA Unity in diversity Indonesia and Infectious Diseases – a Great Challenge to Mitigate Biorisk Problems with emerging and reemerging infectious diseases Most caused mainly by environmental, ecological or demographic factors spread by travel and trade – Indonesia is a maritime country with 17.504 islands, 700 languages, 33 provinces, 230 million population Problems with people movement Recognize the need to develop, strengthen and maintained the capacity to detect, report and respond to public health events WHAT ARE WE FACING? Indonesia – A very diverse populations – vast genome diversity – disease management complex Indonesia - A rapidly developing country with serious challenges in infectious (emerging and re-emerging) and zoonotic diseases New, re-emerging or drug-resistant infections whose incidence in humans has increased within the past two decades or whose incidence threatens to increase in the near future Indonesia – A rapidly developing country with serious problems in Infectious disease Malaria: 15 million cases and 42,000 deaths/year (2005) - highest case number and fatality rate in the world; increasing drug resistant parasites Tuberculosis: ranked third in TB burden following India and China - TB is third major causes of mortality Estimation: 269 TB cases/100,000 Dengue: Most important viralborne disease 2004: 78,690 cases (CFR- 1.2%) 2007: 123,174 cases,1,251 deaths Hepatitis B: 10% of population are carriers Moderate-to-high endemic (WHO) DENV SEROTYPE DISTRIBUTION – SHOWED DIVERSITY Management of Disease is Not Simple, Need a Strong Disease Surveillance 250000 C A S E 200000 150000 100000 50000 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Indonesia South-east Asia Region Palembang 1998 Jayapura 1994 Jakarta 2004 8% 8% Yogyakarta 1996 20% 19% Bandung 2002 Four antigenically distinct serotypes: infection with one serotype does not provide protection to the other three 42% 41% 30% 32% Makassar 2007-2008 N = 111 Corwin 2001; Suwandono 2006; Porter 2005; Graham 1999; Richards 1997; Sukri 2003 Merauke 2001 4 1 3 2 Serotype Legend SCIENCE & TECHNOLOGY IN HEALTH SECURITY – PREPAREDNESS FOR PANDEMIC RISK ASSESSMENTS Molecular Epidemiology: • Cluster of viral isolates will indicate the presence of new strain • Surveillance - tracing sources of infection Characteristics of Virus • Alteration of interaction with host receptors - pandemic need changing in specificity of viral type receptor into human-type • Change of virulence • Drug resistance ALL ABOUT COLLABORATION • Interdisciplinary collaboration between genetics, language, culture and medicine Medicine Anthropology Archeology Linguistic Genetics Mathematic THE AUSTRONESIAN DIASPORA WMP OCEANIC WMP SHWNG CMP PAPUA OCEANIC One of the world largest language group. Covers a very wide area, from Madagascar Island as the western most to the Easter Island of Polynesia Eijkman Institute EIJKMAN INSTITUTE and THE POPULATION STRUCTURE of the INDONESIAN ARCHIPELAGO • More than 6,000 samples collected • More than 3745 individuals from 35 ethnic populations examined for mtDNA • 2000 genetic samples from 25 isolated populations of 13 islands for Y STR • Most extensive database on mtDNA sequence polymorphisms in Indonesian archipelago • Pan Asia SNP initiative – mapping 50K Asian population using DNA microarray – 234 Indonesian samples • 200 male samples of Javanese and Batak origin for Rapidly Mutating YSTR • Forensic population database – STR marker 21 loci, Y filer MtDNA and Y chr diversity of 2740 individuals, 70 communities, 12 islands Indonesian genetic diversity is a direct outcome of complex history of immigration, transitory migrants and populations Tumonggor et al. J Hum Genet. 2013: 58 SETTLEMENT of ISLAND SOUTHEAST ASIA THE FIRST WAVE: FROM AFRICA TO THE EAST ~50,000 ya Mellars P (2006). Science The first stage of Indonesian prehistory represent the archipelago’s initial settlement as part of Africa dispersal ~ 50kya SETTLEMENT OF ISLAND SOUTHEAST ASIA THE SECOND WAVE: THE AUSTRONESIAN EXPANSION ~8,000 ya Taiwan ~6,000 ya Austronesians Polynesia Madagascar ~50,000 ya Neolithic movements into and around island SEA – may involve population dispersals from (into) Taiwan, and between Indonesian island groups The largest survey of Indonesian Y chromosome showed the presence of multiple genetic strata that likely arose through a series of distinct migratory process Paternal gene pool subdivided eastern and western part of Indonesia • 1928 individuals - 73 populations, 11 language families • Autosomal marker 50K - HUGO Pan-Asian SNP Consortium -. Science 326, 1541 (2009) • Autosomal data strongly support large demographic movements of Asian populations into eastern Indonesia from around 4 kya (Xu et al & HUGO Pan-Asian SNP Consortium, PNAS 109, 4574 (2012) East Papuan and Alorese Sumba, Flores, Lembata Malay,Sumatra, Borneo, Java (Mix with Austroasiatic) VARIATION OF GENOTYPIC PATTERN OF DISEASES HEPATITIS AND OVALOCYTOSIS AS A MODEL • • • Variation of ethnics in Indonesia: 1. The peopling of the Indonesian archipelago using mitochondrial-DNA, Y and autosomal chromosome 2. Anthropological and linguistic study Consistent with cultural and linguistic characteristics Variation of susceptibility and resistance to disease (malaria, TB and others) Variation of genotypic and phenotypic pattern of diseases (infectious and non-infectious, including hepatitis B/C, dengue,red blood cell disorders ) HEPATITIS B VIRUS GENETIC HETEROGENEITY Ten HBV genotypes - A to J have been identified worldwide Shows different geographical distribution, viral characteristics and possibly clinical outcomes and response to treatment, , provide historical information pattern of the local population A: North-west Europe, North America, Central Africa; B: Southeast Asia; C: Far east; D: Mediteranean, Middle East, India; E: Sub-Saharan Africa; F: American natives, Polynesian; G.USA samples, H: Mexico Miyakawa & Mizokami, Intervirology 2003;46:329-338 • Indonesian Archipelago: Genotypes B and C are predominant, with subgenotype B3/adw unique to Indonesia • Latin America: Genotypes F and H are indigenous in this continent, genotypes A and D might be a mere reflection of a past European migration, and genotypes B and C could represent a consequence of a recent Asian migration. HEPATITIS B VIRUS GENOTYPE DISTRIBUTION IN INDONESIAN ARCHIPELAGO Nanning Shanghai Korea Hongkong Japan Taiwan Bangkok Chinese Indonesian Philippines A1 Medan C1 C2 East Asia Padang Kotamoba gu C5 Philippines Dayak Benuaq B1 Japan Mandar, Toraja B2 China B3 West Indonesia B5 Philippines Alor Nias & Mentawai B9 Merauk e Nusa Tenggara islands of Indonesia Java East Flores Mataram D1 D3 Jayapur a Sentani Kajang, Makasar B7 B8 Ternate, Ambon Sumba West Flores A 100 100 68 100 100 B 100 100 97 92 100 100 AB033553C2 AB113879C2 AB202071C2 AP011098C2 X01587C2 92 92 C 100 D 100 99 G 100 100 F 100 100 0.02 H E 100 AB032431E AB205129E AB106564E X75657E AB064311G AB064312G EF634480G AB056513G AB086397F1 AF223963F1 AF223962F2 AF223965F2 AB166850F2 AB214516F2 AY090455F1 AB179747H AB205010H AB266536H AB059660H 100 100 Inuit populations in Arctic Japanese, east Asia B1 B2 B3 B7 B9 B5 B8 B4 C1 C2 Chinese, Asia mainland Indonesian populations, Southeast Asia Indonesian populations, Southeast Asia Indonesian populations, Southeast Asia Philippino and Indonesian populations, Southeast Asia Indonesian populations, Southeast Asia Vietnamese, Southeast Asia East Asia, China mainland and Southeast Asia East Asia, China mainland and Southeast Asia PhLC14C5 PhLC03C5 AB241112C5 100 AP011101C5 AP011099C5 AP011100C5 PhCH24C5 M154 AP011105C7 AP011104C7 AP011107C7 AP011106C7 96 AP011108C J022 STN013 AB493837 AB493847 AB493838 100 AB493840 AB493839 AP011102C6 AB105172 AB493844 AB493843 AB493842 100 AB493841 100 AP011103C6 M007 X75656C3 X75665C3 100 AB048705C4 AB048704C4 100 AF280817D1 AY161157D1 100 AY161150D1 M73D1 AF151735D1 100 AB078032D2 AB078033D2 AB090268D2 AB090269D2 100 100 AY090452D3 AB493848. AB493845 AB493846 DQ315776D3 100 DQ315777D3 100 AB048702D4 AB048703D4 100 AB048701D4 AB033559D4 92 92 B6 AP011089B7 AB493833 100 AB493835 AB493836 AB493832 EIHB134B3 AB033555B3 AP011085B3 AB033554B3 D00331B3 2059B3 1839B3 M54923B3 LBY01B7 100 LBY041B7 Alr049B7 AP011090B7 LBY009B7 AP011091B7 FLT32B7 AP011092B7 100 KD048B7 CBL027B7 100 LAR070B7 AP011088B7 FLT020B7 100 AB493830 AB493828 AB493829 AB493827 AB493831. 100 KDI35B8 KDI43B8 100 KDI04B8 KD35B8 AB219426B5 AB219429B5 100 AB219427B5 AB219428B5 AP011087B5 100 AP011086B5 PAN09B9 PAN011B9 Alo36B9 100 PAN01B9 PAN037B9 AP011096B8 AB493834 100 AP011093B8 AP011095B8 100 AP011094B8 AY033073B4 AY033072B4 AB100695B4 AB073835B4 AB112066C1 AB112348C1 AB112471C1 AB074756C1 EIHB006C1 AP011097C1 SLK-126 92 92 A1 A2 DQ463787B6 DQ463790B6 DQ463791B6 DQ463792B6 DQ463788B6 DQ463793B6 DQ463794B6 DQ463789B6 D23678B1 AB073850B1 AB073848B1 D00329B1 DQ993700B2 EU139543B2 DQ993708B2 EIH21AB2 2061B2 DQ993711B2 EIH45AB2 AP011084B2 92 100 AY226578 M57663A1 AB246335A1 AB241115A1 AF297621A1 X70185A2 AB222707A2 AB126580A2 AB246337A2 100 C5 C7 C6 Philippino, East Asia Indonesian populations, Southeast Asia Indonesian populations, Southeast Asia C3 Polynesia, New Caledonia, Pacific region C4 Aborigine populations, Southern Australia D1 D2 D3 D4 E G F1 F2 H Figure 2 a * * Indonesian of Chinese ethnic origin B9 B7 B5 B3 B9 B7 B3 Makasarese C2 B2 C2 C1 B7 B5 B3 C5 C2 C1 Torajan and Mandar Batak b C5 B3 C1 Minahasa and Talaud B7 Ternate and Ambonese B9 B8 B5 B3 Nias and Mentawai B9 B8 B5 B3 B2 C2 C1 Minang B3 C2 Malay B9 B7 B5 B9 B8 B3 C1 B5 B3 B2 Javanese C2 C1 Indonesian of Chinese ethnic origin B9 B2 B9 B7 B5 B3 B8 B3 C1 Balinese and Lombok B7 B5 C2 C1 Sumbanese B9 B8 B7 B5 B3 Flores C2 C1 Alorese C6 B7 C2 B3 C1 C2 C1 Papuan HBV genotype is maintained in Javanese ethnic population separated for centuries HBV/B3 (adw) Javanese (Holland) Javanese (Suriname) Javanese (Java) TWO TYPES HBV/C SUBGENOTYPES: THE ASIAN AND PAPUA-PACIFIC (study on HBV isolates from the Asia-Pacific Region) Papua-Pacific GQ358156 AB493842 AB493840 GQ358155 AB493844 AB493838 AP011103 AB493837 AB493841 AP011105 AB493839 AP011104 GQ358157 AP011102 AP011107 AP011108 EU670263 AP011106 AP011099 7 AP011101 X75656 6 9 X75665 3 AB048705 North Australia 8 4 AP011100 PhLC14 AB048704 H 5 AB266536 PhLC03 10 AB241112 PhCH24 AB540583 2 1 AF223957C1 AB202071 EAST ASIA AND SEA AP011098 AP011097 AY247031 AB113879 AB112471 AB033553 AF533983 AB074756 D23681 AF068756 X01587 AB112066 100 AB112348 AF223960 HBV genotype is maintained in Javanese ethnic population separated for centuries • Subgenotypes of HBV/B in Indonesia: – B3 (adw) – B5 (adw) – B7 (ayw) – B2 (Chinese Indonesian) DNA Sequence: • Subgenotypes of HBV/B in Japan (Sugauchi et al): – Bj – B2 (Ba: prevalent in China) Maintained Viral Characteristics In Chinese ethnic population* Clinical Implications? *Have been living in Indonesia for > 3 generations CLINICAL AND PUBLIC HEALTH SIGNIFICANCE: Detection failure of HepB virus in blood donors 309 regular blood donors (2005) from Medan (North Sumatra) and Solo (Central Java) (HBsAg, anti-HCV and anti-HIV neg) • anti-HBc (+) : 134 (43.4%) • HBV DNA (+): 25 (8.09%) • Variants were detected in 7 samples: T123A (1), M133L (1), T143M (7) ‘a’ determinant (124-147) Thedja MD et al. 2010. Occult hepatitis B in blood donors in Indonesia: alter antigenicity of the hepatitis B virus surface protein. Hepatology Int.4, 608 • Malaria - caused by Plasmodium parasites- is responsible for high mortality mortality. An estimated 300-500 million cases each year result in more than 1 million deaths • Available preventive methods are not sufficient • Humans have a number of genetic adaptations that act to combat Plasmodium • Understanding the mechanism of malaria interactions with the erythrocytes membrane will provide opportunities for new methods of disease prevention and treatment Rank 49 Country INDONESIA Mortality Rate 3.1 MALARIA AS A SELECTIVE AGENT IN HUMANS Duffy negativity, G6PD deficiency (A-), HbS, HbC WHO 2005 SAO, HbE, Gerbich negativity, α-thalassemia (many), G6PD deficiency (many) COMMON THEMES AMONG MALARIARESISTANCE ALLELES EXAMINED to DATE (G6PD A-, HBC, HBS, DUFFY NEGATIVITY, HBE) 1) Recent origins (<<30,000 years) 2) Strong selection coefficients 3) Compatible with “Malarial Eve” Hypothesis SOUTHEAST ASIA OVALOCYTOSIS • • • • An uncommon variant of hereditary elliptocytosis Caused by heterozygosity for a 27 bp del in the gene encoding the erythrocyte membrane protein band 3 – the solute carrier family 4 (SLC4A1) protein on chromosome 17 SAO erythrocytes are rigid because mutation enhances the tightness of association between band 3, ankyrin and the spectrin lattice The condition confers highly specific protection against cerebral malaria Erythrocyte membrane contain variety of proteins – (i) peripheral proteins of bands 1, 2, 4.1, 4.2, 5 and 6, and (ii) integral proteins of bands 3, 7 and PAS 1 - 4. Mutation in SLC4A1 gene enhances the tightness of association between band 3, ankyrin and spectrin lattice SAO PROTECTS FROM MALARIARELATED MORTALITY. • Strong correlation between SAO and malaria prevalence (Mgone et al. 1996). • Case-control studies suggest strong (complete?) protection from cerebral malaria (Genton et al. 1995, Allen et al. 1999). SAO is A BALANCED POLYMORPHISM Heterozygote has greatly enhanced fitness in malarial environments. Heterozygotes have no negative clinical manifestations. SAO homozygote is inviable When SAO is common, it can demonstrably increase the miscarriage rate (Liu et al. 1994) SAO as a health burden One in for of the pregnancies in these couples will be lost due to SAO inviability. With random mating 12.25% (=0.35x0.35) of couples will both be heterozygous carriers of SAO. SAO HAS A RESTRICTED GEOGRAPHIC DISTRIBUTION. GEOGRAPHICAL DISTRIBUTION of SAO in INDONESIAN ARCHIPELAGO (as 2014) 0 0 4.6 8.6 1.8 0 3.3 4 6.6 4.6 0 0 0.9 30 27.2 11 0 2.6 20 1.4 2.9 10.5 13.4 0 FREQUENCY OF SAO VARIES SIGNIFICANTLY IN DIFFERENT POPULATIONS (not revised) Africa 13.4 Alor 27 Irian Batak 0 Java 0 0 Makassar 2.9 Sasak 0 Bugis 0 Minahasa 10.5 Sumba Sumbawa 0 Toraja 0 6.6 Kaili 0.9 Banjar 4.6 Palembang 0 Tengger Dayak 3.3 Minang 1.8 Malay (P’baru) 0.1 8.6 Bali 1.4 0 10 20 FREQUENCY OF SAO (%) 30 Eijkman Institute DISTRIBUTION OF PAPUAN GENETIC CONTRIBUTION AND SAO PREVALENCE SAO Prevalance (%) 50 40 SAO is not found in nonendemic area for malaria; but not all endemic area shown SAO 30 20 10 0 0 5 10 15 20 25 30 Papuan Genetic Contribution (%) •SAO is found mainly in two clades: a. Malay-related (low prevalence) and b. Papuan-related (high prevalence) Models of Coevolution between Plasmodium and Humans May Need to Accommodate the Existence of Ancient Malaria-resistance Alleles P. falciparum emerges as health threat ~10,000 years before present. SAO likely evolved after expansion of P. falciparum into Southeast Asia. FUTURE STUDY Bringing human and medical genetics and computational biology together – to answer the big question on how culture shaped the human genome The answer is in your hands Medicine Anthropology Archeology Linguistic Genetics Mathematic Acknowledgment Steve Lansing, Complex Institute, NTU Murray Cox and Elsa Guillot, Massey University, New Zealand Tatyana Karafet, University of Arizona The HUGO Pan-Asian SNP Consortium EIJKMAN INSTITUTE David Mulyono, Meta Dewi Tedja Din Syafruddin Helen Suryadi Safarina Malik Gludhug Purnomo Windy Joanmawati Alida Harahap Dewi Megawati Thank you and greetings from Indonesia