Genetic diversity of HLA system in six populations from Mexico City Metropolitan Area, Mexico: Mexico City North, Mexico City South, Mexico City East, Mexico City West, Mexico City Center and rural Mexico City

Abstract

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1217 Mexicans from the Mexico City Metropolitan Area living in the northern (N = 751), southern (N = 52), eastern (N = 79), western (N = 33), and central (N = 152) Mexico City, and rural communities (N = 150), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes include 11 Native American haplotypes. Admixture estimates revealed that the main genetic components are Native American (63.85 ± 1.55% by ML; 57.19% of Native American haplotypes) and European (28.53 ± 3.13% by ML; 28.40% of European haplotypes), and a less apparent African genetic component (7.61 ± 1.96% by ML; 7.17% of African haplotypes).

Introduction

With over 20 million inhabitants, Mexico City is the largest city in the Western Hemisphere [1]. Mexico City has more inhabitants than most countries. The Metropolitan Area of Mexico City (MAMC) has grew so large now that the City of Mexico itself [formerly known as Federal District (abbreviated D.F. in Spanish)], 60 municipalities from the State of Mexico and one municipality from the state of Hidalgo are considered part of the MAMC (Fig. 1). It's the most densely populated area in the country. As of 2016, 75% of the State of Mexico's population, or approximately 10 million people, lives in a municipality that is part of the MAMC [2]. Overall, 25,106,261 persons live in the area conformed by the State of Mexico and Mexico City [3], [4]. As of 2015, 33% of people living in the State of Mexico were born in a different state [3], while 18% of people living in Mexico City were born in a different state [4], indicative of the strong attraction effect for the internal migrant population. In the State of Mexico, three of every 100 inhabitants of 3 years and over are speakers of a native language. The most common indigenous languages in the state are: Mazahua (29.6%) and Otomí (25.4%). Around 17% of the population of the state is considered indigenous and 1.9% self identifies as Afro-descendant [3]. In the case of Mexico City, two of every 100 inhabitants of 3 years and over are speakers of a native language. The most common indigenous languages in the MACM are: Nahuatl (29.8%) and Mixtec (12.3%). Around 8.8% of the population of the entity is considered indigenous, and 1.8% self identifies as Afro-descendant [4]. Mexico City is home to large numbers of immigrants from Canada, the United States, South America, Central America, the Caribbean, Europe and the Middle East. Most recently, there has been an influx of immigrants from Asia-Pacific countries like South Korea and China [5], [6].

The region occupied by present-day MAMC has been inhabited at least for the past 10,000 years [7]. Recently found remains close to what would be the shore of the ancient lake that was dried by Spanish conquerors account for Pre-Classical occupation of the Valley of Mexico. The burial site dates back to 700–400 BCE and was part of a village that lasted for at least 500 years, making it more than a transitory settlement [8]. Evidence for larger occupation centers can be found in more recent times: more than a thousand years before the apogee of Mexica culture, an older culture had built pyramids and temples on the shores of the ancient lake of Cuicuilco (460 CE), now situated in the southern part of Mexico City [9]; Before the Mexica dominated the region, a civilization built around the city of Teotihuacan was in power. The ancient city of Teotihuacan (200–600 CE), located in the Basin of Mexico, was constituted as a multiethnic civilization and of greater influence in Mesoamerica during the Classic period. In this way, the population made up of local and foreign individuals was organized in neighborhoods, which differed in maintaining a close relationship with their ethnic group of origin and for specializing in one or more trades, although there is evidence of only temporary occupation at least in the first phases of occupation [10]. The first Spaniards who arrived at the beginning of the 16th century encountered the Mexica (often referred to as Aztec) culture that built the city and ceremonial temples on the shores of a series of lakes and on reclaimed land. According to tradition, Metzxicco-Tenochtitlan was built right at the site where pilgrims from Aztlán (probably located in northwestern Mexico) found the sacred cactus growing on a rock, and on which an eagle perched with its wings outstretched in the sun, devouring a snake. Their most famous temple, Templo Mayor, was dedicated to gods Huitzilopochtli and Tlaloc. Although humble, for it was built with mud and wood, marked the beginning of what would eventually be one of the most famous ceremonial buildings of its time. One by one the rulers of Mexico-Tenochtitlan left as a testimony of their devotion a new constructive stage on that pyramid. The accounts given by Hernán Cortés [11] on the size and urban development of the city provide an idea of the extension and demographic characteristics of Mexico-Tenochtitlan: “This great city of Temixtitan [Mexico] is situated in this salt lake, and from the main land to the denser parts of it, by whichever route one chooses to enter, the distance is two leagues […] The city is as large as Seville or Cordova; its streets, I speak of the principal ones, are very wide and straight […] This city has many public squares, in which are situated the markets and other places for buying and selling. There is one square twice as large as that of the city of Salamanca”. Spanish people then and now find overwhelmingly impressive the magnitudes, the amounts, the distances: “Mexico City is huge: moving in it is a challenge that is renewed every day […] Millions and millions who live in remote neighborhoods and do not have a car leave their homes every morning before dawn to walk to a bus that brings them to the subway […] and then sometimes another bus […]. Millions who live in more or less remote neighborhoods and have cars leave at dawn to cross roads […] usually one or two hours one way, others back, sit down, alone. Thousands of people who live in elegant neighborhoods and have a car and have a driver […] dispatch their affairs in their cars, read, talk, solve [problems while traveling in] their cars; the time is long but you can use it” [1].

Established as the capital city for the Viceroyalty of New Spain, very early in the colonial period Mexico City became an attractor center to immigrants from all over the territory, a status it has maintained for around 500 years. Some figures on the number of inhabitants establish the population size at around 5–10 million inhabitants by 1518 [12], declining to only 1.4 ± 0.3 million of Native Americans shortly after the beginning of the Colonial period [13]. In the context of internal migration within Mexico, immigration into the MAMC is one of the most important processes that has occurred in the country’s history [14]. Between 1950 and 1980 the population in the MAMC increased by approximately 4.5 million [15]. A large proportion of immigrants have opted to settle in the northeastern and eastern part of the megalopolis: between 1950 and 1980 the population living in those regions grew from approximately 233,000 to over 5 million people [16]. An increase of 11 million persons in the MAMC population occurred over the past 30 years, with around 9.2 million inhabitants settling in northern Mexico City alone, bringing to the MAMC a predominantly Native American component, given the demographic characteristics of MAMC immigrants (mostly Hidalgo, Puebla, Tlaxcala and Oaxaca) [14], [17].

For the present work, we analyzed HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) PCR-SSP based typings in 1217 mixed ancestry Mexicans from the Metropolitan Area of Mexico City (MAMC) [includes the State of Mexico and is composed by the following populations: Mexico City North, N = 751, Allele Frequencies Net Database Identifier (AFND-ID): 3474; Mexico City Center, N = 152, AFND-ID: 3476; Mexico City South, N = 52, AFND-ID: 3473; Mexico City East, N = 79, AFND-ID: 3475; Mexico City West, N = 33, AFND-ID: 3454; Mexico City Rural, N = 150, AFND-ID: 3589]. Although one municipality from the state of Hidalgo is considered itself part of the MAMC, no individuals from this municipality form part either of MAMC sample sets or Hidalgo sample sets and thus sample sets from the state of Hidalgo are analyzed in a separate article in this same issue. In addition to the individual populations we also show data for these combined populations. The latter are not held on AFND to prevent duplication of data. Maximum-likelihood (ML) frequencies for alleles and four-locus haplotypes were estimated using an Expectation-Maximization algorithm. For a comprehensive review on the methods, such as sample collection, HLA typing and statistical analyses, please refer to [18] in this same issue. For the frequencies of HLA-A, -B, -DRB1 and -DQB1 and haplotypic data for the sample sets of the MAMC please refer to the Supplementary Information: Supplementary Tables 1–11. For data on Hardy-Weinberg equilibrium (HWE) please see Supplementary Information: Supplementary Table 12 of this work and Supplementary Information: Supplementary Table 9 in [18] in this same issue. We found that the most frequent haplotypes for the state (haplotypic frequency, H.F. ≥ 1.0%, arbitrarily; Supplementary Table 5) are all Native American haplotypes (HLA ~ A*02 ~ B*39 ~ DRB1*04 ~ DQB1*03:02, A*02 ~ B*35 ~ DRB1*08 ~ DQB1*04, A*68 ~ B*39 ~ DRB1*04 ~ DQB1*03:02, A*02 ~ B*35 ~ DRB1*04 ~ DQB1*03:02, A*24 ~ B*39 ~ DRB1*14 ~ DQB1*03:01, A*24 ~ B*35 ~ DRB1*04 ~ DQB1*03:02, A*24 ~ B*39 ~ DRB1*04 ~ DQB1*03:02, A*02 ~ B*15:01 ~ DRB1*04 ~ DQB1*03:02, A*02 ~ B*15:01 ~ DRB1*08 ~ DQB1*04, A*02 ~ B*40:02 ~ DRB1*04 ~ DQB1*03:02 and A*31 ~ B*35 ~ DRB1*08 ~ DQB1*04). The first six of them can also be found in previous reports depicting HLA haplotypic diversity in Mexico City (MC) in frequencies above 1% [19], [20], [21]. Admixture estimates (Fig. 1) revealed that the main genetic components are Native American (63.85 ± 1.55% by the ML method and 57.19% of Native American haplotypes) and European (28.53 ± 3.13% by the ML method and 28.40% of European haplotypes), and less apparent African genetic component (7.61 ± 1.96% by the ML method and 7.17% of African haplotypes). These results are similar to those previously reported by several authors using diverse genetic estimators (Table 1), but, in line with previous reports [22], the ancestral proportions vary considerably among the different subsets sampled: from MC Center (47.70 ± 1.16% by the ML method and 40.91% of Native American haplotypes) and MC East (53.31 ± 17.08% by the ML method and 60.00% of Native American haplotypes) with the lowest estimations, to MC West (62.11 ± 7.09% by the ML method and 55.88% of Native American haplotypes), MC North (74.21 ± 4.91% by the ML method and 70.78% of Native American haplotypes) and MC South (79.39 ± 1.76% by the ML method and 75.96% of Native American haplotypes); the latter two showing a higher Native American component than the rural areas (64.51 ± 3.54% by the ML method and 56.58% of Native American haplotypes). For both MC North and South, the high proportion of the Native American component correlates with a higher presence of indigenous persons in these regions, because of recent migration (northern MC) [14], [17] or to the presence of local indigenous groups such as the Nahua (southern MC) [23]. The European component follows the exact opposite pattern, with the lowest estimations in MC South (17.75 ± 8.29% by the ML method and 19.23% of European haplotypes), MC North (22.27 ± 4.63% by the ML method and 18.99% of European haplotypes) and MC West (28.41 ± 12.29% by the ML method and 30.88% of European haplotypes) below the estimate for the rural areas (30.69 ± 5.05% by the ML method and 26.64% of European haplotypes), and MC East (39.01 ± 16.54% by the ML method and 26.25% of European haplotypes) and MC Center (47.61 ± 2.81% by the ML method and 38.64% of European haplotypes) with higher estimates than those found in the rural areas. Socio-economic stratifications within the urban settlement (i.e. differential salary income, availability of housing credits, amenities, and other economic factors) [22], [24], [25], [26] might explain the stronger European component in the central part of MC, while in the eastern MC it may be explained by earlier settlements, probably dating back to the early colonial period. The migration within the MAMC is highly related to the housing market in the Central Region. The municipalities that received the most housing credits attracted immigrants to a greater extent. The cases of the central municipalities of the metropolitan area stand out, because in them there is a strong real estate supply and there a large number of people have settled in the last part of the 20th century and beginning of 21st century as well. Some of the urban municipalities of the MAMC have experienced an increased dynamism in the construction of houses, mainly those located in the western MAMC region, in the area of influence of the Metropolitan Area of Toluca (part of the state of Mexico). Migration is closely related to regional factors. Not only the wage difference between regions, but a whole series of phenomena such as the supply of employment, the supply of housing, the search for better living conditions and urban growth attract the population [27].

The African component is less prominent and with no specific pattern [MC South (2.87 ± 9.05% by the ML method and 2.89% of African haplotypes), MC North (3.52 ± 1.21% by the ML method and 5.45% of African haplotypes), MC Center (4.69 ± 1.71% by the ML method and 8.77% of African haplotypes), MC rural areas (4.79 ± 1.93% by the ML method and 5.92% of African haplotypes), MC East (7.68 ± 10.61% by the ML method and 4.38% of African haplotypes), and MC West (9.48 ± 7.67% by the ML method and 2.94% of African haplotypes)]. Asian haplotypes (5.20% of the haplotypic diversity present in the region) are present in all datasets with no specific pattern [MC South (1.92%), MC North (3.65%), MC East (5.63%), MC West (5.88%), MC rural areas (7.24%) and MC center (8.77%)]. Relative isolation in the southern areas, inhabited by indigenous communities that still maintain their identities and traditions; strong immigration dynamics in northern MC with immigrants coming mainly from states with high contribution of Native American ancestry [22]; persistence of colonial period and modern Mexico demographic signatures in the center (specially Asian migration, but also other groups like Jews and Lebanese) and eastern zones and recent growth in the west and the rural areas are present in the genetic variation found in the Mexico City subsets of samples analyzed [28]. All data from our sample sets, both frequencies and individual genotypes, can be found at The Allele Frequency Net Database website (www.allelefrequencies.netwww.allelefrequencies.net) [29].